GenVue Discovery
GenVue Discovery
Curation
Showing variants that contain the term
Below are conditions that were reviewed by an expert panel and/or are in the Genetic Testing Registry (GTR) according to ClinVar. The data presented does not diagnose disease and has no guarantees of reporting accuracy. We report heterozygous variants as yellow and homozygous variants as red. A red or yellow variant does not necessarily mean one has or carries a condition or disease. This is for research and educational purposes only.
Gene:
CASP8
Variant:
c.904G>C
(p.Asp302His)
rsID: rs1045485
Ref Allele: G
Alt Allele: C
Freq: 9.6458%
CADD: 0.076
ClinVar Submissions (3)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign, protective
Assembly: GRCh38
Chromosome/Position: 2:201284866
OMIM Allelic Variant: 601763.0003
Caspase 8 deficiency is a syndrome of lymphadenopathy and splenomegaly, marginal elevation of 'double-negative T cells' (DNT; T-cell receptor alpha/beta+, CD4-/CD8-), defective FAS-induced apoptosis, and defective T-, B-, and natural killer (NK)-cell activation, with recurrent bacterial and viral infections (summary by Madkaikar et al., 2011).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign, protective
Assembly: GRCh38
Chromosome/Position: 2:201284866
OMIM Allelic Variant: 601763.0003
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign, protective
Assembly: GRCh38
Chromosome/Position: 2:201284866
OMIM Allelic Variant: 601763.0003
Insufficiently evaluated protective — Associated with protection against breast cancer.
Expert Reviewed Benign/Likely benign, protective
Hetero
Gene:
MTHFR
Variant:
c.1286A>C
(p.Glu429Ala)
rsID: rs1801131
Ref Allele: T
Alt Allele: G
Freq: 24.9092%
CADD: 19.91
ClinVar Submissions (6)
Last Evaluated: May 02, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11794419
OMIM Allelic Variant: 607093.0004
Last Evaluated: May 02, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11794419
OMIM Allelic Variant: 607093.0004
Last Evaluated: May 02, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11794419
OMIM Allelic Variant: 607093.0004
Last Evaluated: May 02, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11794419
OMIM Allelic Variant: 607093.0004
Last Evaluated: May 02, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11794419
OMIM Allelic Variant: 607093.0004
Last Evaluated: May 02, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11794419
OMIM Allelic Variant: 607093.0004
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Expert Reviewed Conflicting/Uncertain
Hetero
Gene:
BTD
Variant:
c.1336G>C
(p.Asp446His)
rsID: rs13078881
Ref Allele: G
Alt Allele: C
Freq: 2.5667%uncommon
CADD: 23.3
ClinVar Submissions (15)
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
This individual has one copy of the genetic mutation, and because it's autosomal recessive, they are likely a carrier rather than manifesting the condition. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Low clinical importance, pathogenic — This variant is implicated in partial and profound biotinidase deficiency. Alone, this variant is estimated to have a 52% loss of enzymatic activity. This variant is often found with A171T, and together they are reported to cause profound deficiency. Notably there is a report of asymptomatic double-mutant adults, so symptoms may have variable penetrance. This variant is found compound heterozygously with more serious mutations in cases of partial biotinidase deficiency.
Expert Reviewed Clinically Significant Conflicting/Uncertain
Hetero
Gene:
GJB2
Variant:
c.71G>A
(p.Trp24Ter)
rsID: rs104894396
Ref Allele: C
Alt Allele: T
Freq: 0.0016%rare
CADD: 43
ClinVar Submissions (17)
DFNX2, also known as DFN3, is an X-linked recessive disorder characterized by progressive conductive and sensorineural hearing loss and a pathognomonic temporal bone deformity that includes dilatation of the inner auditory canal and a fistulous connection between the internal auditory canal and the cochlear basal turn, resulting in a perilymphatic fluid 'gusher' during stapes surgery (summary by de Kok et al., 1995 and Song et al., 2010). See also choroideremia, deafness, and mental retardation (303110), a contiguous gene deletion syndrome involving the POU3F4 and CHM (300390) genes on Xq21; isolated choroideremia (303100) is caused by mutation in the CHM gene.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
Nonsyndromic hearing loss and deafness, DFNA3 is characterized by pre- or postlingual, mild-to-profound progressive high-frequency sensorineural hearing impairment. Affected individuals have no other associated medical findings.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
Nonsyndromic hearing loss and deafness, DFNA3 is characterized by pre- or postlingual, mild-to-profound progressive high-frequency sensorineural hearing impairment. Affected individuals have no other associated medical findings.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
Nonsyndromic hearing loss and deafness (DFNB1) is characterized by congenital non-progressive mild-to-profound sensorineural hearing impairment. No other associated medical findings are present.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
Nonsyndromic hearing loss and deafness (DFNB1) is characterized by congenital non-progressive mild-to-profound sensorineural hearing impairment. No other associated medical findings are present.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
A decreased magnitude of the sensory perception of sound. [HPO:probinson]
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
A partial or complete loss of hearing in one or both ears. It is classified as conductive, sensory, or central.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
Hystrix-like ichthyosis with deafness (HID) is a disorder characterized by dry, scaly skin (ichthyosis) and hearing loss that is usually profound. Hystrix-like means resembling a porcupine; in this type of ichthyosis, the scales may be thick and spiky, giving the appearance of porcupine quills.Newborns with HID typically develop reddened skin. The skin abnormalities worsen over time, and the ichthyosis eventually covers most of the body, although the palms of the hands and soles of the feet are usually only mildly affected. Breaks in the skin may occur and in severe cases can lead to life-threatening infections. Affected individuals have an increased risk of developing a type of skin cancer called squamous cell carcinoma, which can also affect mucous membranes such as the inner lining of the mouth. People with HID may also have patchy hair loss caused by scarring on particular areas of skin.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
Palmoplantar keratoderma with deafness is a disorder characterized by skin abnormalities and hearing loss. Affected individuals develop unusually thick skin on the palms of the hands and soles of the feet (palmoplantar keratoderma) beginning in childhood. Hearing loss ranges from mild to profound. It begins in early childhood and gets worse over time. Affected individuals have particular trouble hearing high-pitched sounds.The signs and symptoms of this disorder may vary even within the same family, with some individuals developing only skin abnormalities and others developing only hearing loss.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
Bart-Pumphrey syndrome is characterized by nail and skin abnormalities and hearing loss.People with Bart-Pumphrey syndrome typically have a white discoloration of the nails (leukonychia); the nails may also be thick and crumbly. Affected individuals often have wart-like (verrucous) skin growths called knuckle pads on the knuckles of the fingers and toes. They may also have thickening of the skin on the palms of the hands and soles of the feet (palmoplantar keratoderma). The skin abnormalities generally become noticeable during childhood.The hearing loss associated with Bart-Pumphrey syndrome ranges from moderate to profound and is typically present from birth (congenital).The signs and symptoms of this disorder may vary even within the same family; while almost all affected individuals have hearing loss, they may have different combinations of the other associated features.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
Vohwinkel syndrome is a disorder with classic and variant forms, both of which affect the skin.In the classic form of Vohwinkel syndrome, affected individuals have thick, honeycomb-like calluses on the palms of the hands and soles of the feet (palmoplantar keratoses) beginning in infancy or early childhood. Affected children also typically have distinctive starfish-shaped patches of thickened skin on the tops of the fingers and toes or on the knees. Within a few years they develop tight bands of abnormal fibrous tissue around their fingers and toes (pseudoainhum); the bands may cut off the circulation to the digits and result in spontaneous amputation. People with the classic form of the disorder also have hearing loss.The variant form of Vohwinkel syndrome does not involve hearing loss, and the skin features also include widespread dry, scaly skin (ichthyosis), especially on the limbs. The ichthyosis is usually mild, and there may also be mild reddening of the skin (erythroderma). Some affected infants are born with a tight, clear sheath covering their skin called a collodion membrane. This membrane is usually shed during the first few weeks of life.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
Nonsyndromic hearing loss is a partial or total loss of hearing that is not associated with other signs and symptoms. In contrast, syndromic hearing loss occurs with signs and symptoms affecting other parts of the body.Nonsyndromic hearing loss can be classified in several different ways. One common way is by the condition's pattern of inheritance: autosomal dominant (DFNA), autosomal recessive (DFNB), X-linked (DFNX), or mitochondrial (which does not have a special designation). Each of these types of hearing loss includes multiple subtypes. DFNA, DFNB, and DFNX subtypes are numbered in the order in which they were first described. For example, DFNA1 was the first type of autosomal dominant nonsyndromic hearing loss to be identified.The characteristics of nonsyndromic hearing loss vary among the different types. Hearing loss can affect one ear (unilateral) or both ears (bilateral). Degrees of hearing loss range from mild (difficulty understanding soft speech) to profound (inability to hear even very loud noises). The term "deafness" is often used to describe severe-to-profound hearing loss. Hearing loss can be stable, or it may be progressive, becoming more severe as a person gets older. Particular types of nonsyndromic hearing loss show distinctive patterns of hearing loss. For example, the loss may be more pronounced at high, middle, or low tones.Most forms of nonsyndromic hearing loss are described as sensorineural, which means they are associated with a permanent loss of hearing caused by damage to structures in the inner ear. The inner ear processes sound and sends the information to the brain in the form of electrical nerve impulses. Less commonly, nonsyndromic hearing loss is described as conductive, meaning it results from changes in the middle ear. The middle ear contains three tiny bones that help transfer sound from the eardrum to the inner ear. Some forms of nonsyndromic hearing loss, particularly a type called DFNX2, involve changes in both the inner ear and the middle ear. This combination is called mixed hearing loss.Depending on the type, nonsyndromic hearing loss can become apparent at any time from infancy to old age. Hearing loss that is present before a child learns to speak is classified as prelingual or congenital. Hearing loss that occurs after the development of speech is classified as postlingual.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
This individual has one copy of the genetic mutation, and depending on the condition, this mutation can act as either autosomal dominant or recessive. Thus, they might manifest one condition while being a carrier for another. However, it's important to conduct thorough research before drawing definitive conclusions.
Expert Reviewed Clinically Significant Pathogenic
Hetero
Below are drug responses that were reviewed by an expert panel according to ClinVar. The data presented has no guarantees of reporting accuracy. Heterozygous variants are reported as yellow and homozygous variants as red. Reference alleles may be modified to match risk. While a red or yellow variant could indicate a suboptimal response to drug, it doesn't necessarily mean one won't respond well to it. This is for research and educational purposes only.
Gene:
CYP19A1
Variant:
c.*161T>G
rsID: rs4646
Ref Allele: A
Alt Allele: C
Freq: 70.0545%
CADD: 0.652
ClinVar Submissions (2)
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Insufficiently evaluated pharmacogenetic — associated with response to a drug letrozole in cancer patients
Expert Reviewed drug response
Homo
Gene:
SOD2
Variant:
c.47T>C
(p.Val16Ala)
rsID: rs4880
Ref Allele: A
Alt Allele: G
Freq: 45.7529%
CADD: 12.94
ClinVar Submissions (2)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:159692840
OMIM Allelic Variant: 147460.0001
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:159692840
OMIM Allelic Variant: 147460.0001
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:159692840
OMIM Allelic Variant: 147460.0001
Expert Reviewed drug response
Hetero
Gene:
GP1BA
Variant:
c.482C>T
(p.Thr161Met)
rsID: rs6065
Ref Allele: C
Alt Allele: T
Freq: 12.7891%
CADD: 0.188
ClinVar Submissions (2)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:4933086
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:4933086
Expert Reviewed drug response
Hetero
Gene:
ERCC1
Variant:
c.354T>C
(p.Asn118=)
rsID: rs11615
Ref Allele: A
Alt Allele: G
Freq: 57.5449%
CADD: 1.504
ClinVar Submissions (2)
Last Evaluated: Dec 06, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45420395
Xeroderma pigmentosum (XP) is characterized by: Sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure in ~60% of affected individuals), with marked freckle-like pigmentation of the face before age two years in most affected individuals; Sunlight-induced ocular involvement (photophobia, keratitis, atrophy of the skin of the lids); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma). Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).
Last Evaluated: Dec 06, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45420395
Last Evaluated: Dec 06, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45420395
Last Evaluated: Dec 06, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45420395
Last Evaluated: Dec 06, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45420395
Last Evaluated: Dec 06, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45420395
Expert Reviewed drug response
Homo
Gene:
XRCC1
Variant:
c.1196A>G
(p.Gln399Arg)
rsID: rs25487
Ref Allele: T
Alt Allele: C
Freq: 71.5477%
CADD: 17.31
ClinVar Submissions (1)
Last Evaluated: Dec 07, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:43551574
Last Evaluated: Dec 07, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:43551574
Last Evaluated: Dec 07, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:43551574
Last Evaluated: Dec 07, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:43551574
Last Evaluated: Dec 07, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:43551574
Expert Reviewed drug response
Homo
Gene:
TANC1
Variant:
c.61+13908C>A
rsID: rs264588
Ref Allele: C
Alt Allele: A
Freq: 12.903%
CADD: 0.117
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:159079879
Expert Reviewed drug response
Hetero
Gene:
TANC1
Variant:
c.62-3284C>G
rsID: rs264631
Ref Allele: C
Alt Allele: G
Freq: 14.7084%
CADD: 0.493
ClinVar Submissions (1)
Last Evaluated: Feb 13, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:159094353
Expert Reviewed drug response
Hetero
Gene:
TANC1
Variant:
c.61+6948A>G
rsID: rs264651
Ref Allele: A
Alt Allele: G
Freq: 6.9214%
CADD: 1.72
ClinVar Submissions (1)
Last Evaluated: Feb 13, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:159072919
Expert Reviewed drug response
Hetero
Gene:
MC4R
Variant:
g.60215554C>A
rsID: rs489693
Ref Allele: C
Alt Allele: A
Freq: 34.9667%
CADD: 0.12
ClinVar Submissions (1)
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:60215554
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:60215554
Clozapine is one of the most effective antipsychotics available in the treatment of schizophrenia and the only antipsychotic found to be effective in treatment-resistant schizophrenia. Clozapine is also used to reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder. Compared to typical antipsychotics, clozapine is far less likely to cause movement disorders, known as extrapyramidal side effects, which include dystonia, akathisia, parkinsonism, and tardive dyskinesia. However, there are significant risks associated with clozapine therapy that limits its use to only the most severely ill patients who have not responded adequately to standard drug therapy. Most notably, because of the risk of clozapine-induced agranulocytosis, clozapine treatment requires monitoring of white blood counts and absolute neutrophil counts, and in the US, the FDA requires that patients receiving clozapine be enrolled in a computer-based registry. Clozapine is metabolized in the liver by the cytochrome P450 (CYP) system of enzymes. CYP1A2 is the main CYP isoform in clozapine metabolism and CYP1A2 activity is an important determinant of clozapine dose. Other CYP enzymes involved in clozapine metabolism include CYP2D6 and CYP3A4. Approximately 6-10% of Caucasians have reduced activity of CYP2D6 ("poor metabolizers"). These individuals may develop higher than expected plasma concentrations of clozapine with usual doses. The FDA-approved drug label for clozapine states that a dose reduction may be necessary in patients who are CYP2D6 poor metabolizers.
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:60215554
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:60215554
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:60215554
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:60215554
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:60215554
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:60215554
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:60215554
Expert Reviewed drug response
Homo
Gene:
CHRNA3
Variant:
c.1390-2867C>T
rsID: rs578776
Ref Allele: G
Alt Allele: A
Freq: 41.4795%
CADD: 0.96
ClinVar Submissions (1)
Last Evaluated: Apr 12, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:78596058
Expert Reviewed drug response
Hetero
Gene:
APOA5
Variant:
c.-644C>T
rsID: rs662799
Ref Allele: G
Alt Allele: A
Freq: 89.5929%
CADD: 3.29
ClinVar Submissions (1)
Last Evaluated: May 14, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:116792991
Last Evaluated: May 14, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:116792991
Last Evaluated: May 14, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:116792991
Insufficiently evaluated pharmacogenetic — associated with the triglyceride levels and the risk of first heart attack
Expert Reviewed drug response
Homo
Gene:
SLC28A3
Variant:
c.862-360C>T
rsID: rs885004
Ref Allele: G
Alt Allele: A
Freq: 12.285%
CADD: 5.189
ClinVar Submissions (1)
Last Evaluated: Dec 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 9:84294635
Expert Reviewed drug response
Hetero
Gene:
UGT1A1
Variant:
c.-364C>T
rsID: rs887829
Ref Allele: C
Alt Allele: T
Freq: 34.8847%
CADD: 8.026
ClinVar Submissions (1)
Last Evaluated: Mar 23, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:233759924
Expert Reviewed drug response
Homo
Gene:
NAT2
Variant:
c.282C>T
(p.Tyr94=)
rsID: rs1041983
Ref Allele: C
Alt Allele: T
Freq: 36.3604%
CADD: 0.032
ClinVar Submissions (1)
Last Evaluated: Oct 27, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 8:18400285
Expert Reviewed drug response
Hetero
Gene:
ABCB1
Variant:
c.3435T>C
(p.Ile1145=)
rsID: rs1045642
Ref Allele: A
Alt Allele: G
Freq: 59.2492%
CADD: 0.015
ClinVar Submissions (3)
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Expert Reviewed drug response
Hetero
Gene:
CHRNA3
Variant:
c.645C>T
(p.Tyr215=)
rsID: rs1051730
Ref Allele: G
Alt Allele: A
Freq: 24.3932%
CADD: 22.5
ClinVar Submissions (2)
Last Evaluated: Apr 01, 2015
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:78601997
OMIM Allelic Variant: 118503.0001
Last Evaluated: Apr 01, 2015
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:78601997
OMIM Allelic Variant: 118503.0001
Last Evaluated: Apr 01, 2015
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:78601997
OMIM Allelic Variant: 118503.0001
Expert Reviewed drug response
Hetero
Gene:
CBR3
Variant:
c.730G>A
(p.Val244Met)
rsID: rs1056892
Ref Allele: G
Alt Allele: A
Freq: 39.35%
CADD: 18.79
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 21:36146408
Expert Reviewed drug response
Hetero
Gene:
GATM
Variant:
c.-394-272A>G
rsID: rs1346268
Ref Allele: T
Alt Allele: C
Freq: 33.4942%
CADD: 5.676
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:45380831
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:45380831
Expert Reviewed drug response
Hetero
Gene:
HTR2C
Variant:
c.551-3008C>G
rsID: rs1414334
Ref Allele: C
Alt Allele: G
Freq: 76.7066%
ClinVar Submissions (2)
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: X:114903581
Clozapine is one of the most effective antipsychotics available in the treatment of schizophrenia and the only antipsychotic found to be effective in treatment-resistant schizophrenia. Clozapine is also used to reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder. Compared to typical antipsychotics, clozapine is far less likely to cause movement disorders, known as extrapyramidal side effects, which include dystonia, akathisia, parkinsonism, and tardive dyskinesia. However, there are significant risks associated with clozapine therapy that limits its use to only the most severely ill patients who have not responded adequately to standard drug therapy. Most notably, because of the risk of clozapine-induced agranulocytosis, clozapine treatment requires monitoring of white blood counts and absolute neutrophil counts, and in the US, the FDA requires that patients receiving clozapine be enrolled in a computer-based registry. Clozapine is metabolized in the liver by the cytochrome P450 (CYP) system of enzymes. CYP1A2 is the main CYP isoform in clozapine metabolism and CYP1A2 activity is an important determinant of clozapine dose. Other CYP enzymes involved in clozapine metabolism include CYP2D6 and CYP3A4. Approximately 6-10% of Caucasians have reduced activity of CYP2D6 ("poor metabolizers"). These individuals may develop higher than expected plasma concentrations of clozapine with usual doses. The FDA-approved drug label for clozapine states that a dose reduction may be necessary in patients who are CYP2D6 poor metabolizers.
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: X:114903581
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: X:114903581
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: X:114903581
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: X:114903581
Expert Reviewed drug response
Homo
Gene:
-
Variant:
g.45328787C>T
rsID: rs1719247
Ref Allele: C
Alt Allele: T
Freq: 45.776%
CADD: 3.114
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:45328787
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:45328787
Expert Reviewed drug response
Hetero
Gene:
ABCC4
Variant:
c.3348G>A
(p.Lys1116=)
rsID: rs1751034
Ref Allele: C
Alt Allele: T
Freq: 78.5089%
CADD: 7.895
ClinVar Submissions (1)
Last Evaluated: May 15, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 13:95062722
Expert Reviewed drug response
Homo
Gene:
NAT2
Variant:
c.590G>A
(p.Arg197Gln)
rsID: rs1799930
Ref Allele: G
Alt Allele: A
Freq: 27.0889%
CADD: 18.73
ClinVar Submissions (2)
Last Evaluated: Oct 27, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 8:18400593
OMIM Allelic Variant: 612182.0001
Last Evaluated: Oct 27, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 8:18400593
OMIM Allelic Variant: 612182.0001
Insufficiently evaluated pharmacogenetic — This allele characterizes the NAT2*6A haplotype which causes slow acetylation.
Expert Reviewed drug response
Hetero
Gene:
OPRM1
Variant:
c.118A>G
(p.Asn40Asp)
rsID: rs1799971
Ref Allele: A
Alt Allele: G
Freq: 11.9688%
CADD: 24.2
ClinVar Submissions (2)
Last Evaluated: Apr 20, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:154039662
OMIM Allelic Variant: 600018.0001
Last Evaluated: Apr 20, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:154039662
OMIM Allelic Variant: 600018.0001
Last Evaluated: Apr 20, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:154039662
OMIM Allelic Variant: 600018.0001
Last Evaluated: Apr 20, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:154039662
OMIM Allelic Variant: 600018.0001
Last Evaluated: Apr 20, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:154039662
OMIM Allelic Variant: 600018.0001
Last Evaluated: Apr 20, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:154039662
OMIM Allelic Variant: 600018.0001
Last Evaluated: Apr 20, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:154039662
OMIM Allelic Variant: 600018.0001
Last Evaluated: Apr 20, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:154039662
OMIM Allelic Variant: 600018.0001
Last Evaluated: Apr 20, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:154039662
OMIM Allelic Variant: 600018.0001
Last Evaluated: Apr 20, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:154039662
OMIM Allelic Variant: 600018.0001
Last Evaluated: Apr 20, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:154039662
OMIM Allelic Variant: 600018.0001
Insufficiently evaluated pharmacogenetic — Better clinical outcome with ethanol and naltrexone.
Expert Reviewed drug response
Homo
Gene:
ANKK1;DRD2
Variant:
c.2137G>A
(p.Glu713Lys)
rsID: rs1800497
Ref Allele: G
Alt Allele: A
Freq: 27.1009%
CADD: 7.728
ClinVar Submissions (3)
Last Evaluated: May 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:113400106
OMIM Allelic Variant: 608774.0001
Last Evaluated: May 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:113400106
OMIM Allelic Variant: 608774.0001
Last Evaluated: May 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:113400106
OMIM Allelic Variant: 608774.0001
Clozapine is one of the most effective antipsychotics available in the treatment of schizophrenia and the only antipsychotic found to be effective in treatment-resistant schizophrenia. Clozapine is also used to reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder. Compared to typical antipsychotics, clozapine is far less likely to cause movement disorders, known as extrapyramidal side effects, which include dystonia, akathisia, parkinsonism, and tardive dyskinesia. However, there are significant risks associated with clozapine therapy that limits its use to only the most severely ill patients who have not responded adequately to standard drug therapy. Most notably, because of the risk of clozapine-induced agranulocytosis, clozapine treatment requires monitoring of white blood counts and absolute neutrophil counts, and in the US, the FDA requires that patients receiving clozapine be enrolled in a computer-based registry. Clozapine is metabolized in the liver by the cytochrome P450 (CYP) system of enzymes. CYP1A2 is the main CYP isoform in clozapine metabolism and CYP1A2 activity is an important determinant of clozapine dose. Other CYP enzymes involved in clozapine metabolism include CYP2D6 and CYP3A4. Approximately 6-10% of Caucasians have reduced activity of CYP2D6 ("poor metabolizers"). These individuals may develop higher than expected plasma concentrations of clozapine with usual doses. The FDA-approved drug label for clozapine states that a dose reduction may be necessary in patients who are CYP2D6 poor metabolizers.
Last Evaluated: May 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:113400106
OMIM Allelic Variant: 608774.0001
Last Evaluated: May 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:113400106
OMIM Allelic Variant: 608774.0001
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:113400106
OMIM Allelic Variant: 608774.0001
Last Evaluated: May 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:113400106
OMIM Allelic Variant: 608774.0001
Last Evaluated: May 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:113400106
OMIM Allelic Variant: 608774.0001
Expert Reviewed drug response
Hetero
Gene:
NQO1
Variant:
c.559C>T
(p.Pro187Ser)
rsID: rs1800566
Ref Allele: G
Alt Allele: A
Freq: 22.3528%
CADD: 24.8
ClinVar Submissions (3)
Last Evaluated: Mar 10, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:69711242
OMIM Allelic Variant: 125860.0001
Last Evaluated: Mar 10, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:69711242
OMIM Allelic Variant: 125860.0001
Last Evaluated: Mar 10, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:69711242
OMIM Allelic Variant: 125860.0001
Last Evaluated: Mar 10, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:69711242
OMIM Allelic Variant: 125860.0001
Lung cancer is the leading cause of cancer deaths in the U.S. and worldwide. The 2 major forms of lung cancer are nonsmall cell lung cancer and small cell lung cancer (see 182280), which account for 85% and 15% of all lung cancers, respectively. Nonsmall cell lung cancer can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. Cigarette smoking causes all types of lung cancer, but it is most strongly linked with small cell lung cancer and squamous cell carcinoma. Adenocarcinoma is the most common type in patients who have never smoked. Nonsmall cell lung cancer is often diagnosed at an advanced stage and has a poor prognosis (summary by Herbst et al., 2008).
Last Evaluated: Mar 10, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:69711242
OMIM Allelic Variant: 125860.0001
This individual has one copy of the genetic mutation, and because it's autosomal recessive, they are likely a carrier rather than manifesting the condition. Interpretation of carrier status should be backed by thorough research.
Expert Reviewed Clinically Significant drug response
Hetero
Gene:
FCGR2A
Variant:
c.497A>G
(p.His166Arg)
rsID: rs1801274
Ref Allele: A
Alt Allele: G
Freq: 50.5431%
CADD: 0.08
ClinVar Submissions (3)
Last Evaluated: Mar 28, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:161509955
OMIM Allelic Variant: 146790.0001
Last Evaluated: Mar 28, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:161509955
OMIM Allelic Variant: 146790.0001
Last Evaluated: Mar 28, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:161509955
OMIM Allelic Variant: 146790.0001
Last Evaluated: Mar 28, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:161509955
OMIM Allelic Variant: 146790.0001
Last Evaluated: Mar 28, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:161509955
OMIM Allelic Variant: 146790.0001
Expert Reviewed drug response
Hetero
Gene:
MTRR
Variant:
c.66A>G
(p.Ile22Met)
rsID: rs1801394
Ref Allele: A
Alt Allele: G
Freq: 43.3765%
CADD: 20.7
ClinVar Submissions (6)
Last Evaluated: Jan 30, 2018
Review Status: reviewed by expert panel
Number of Submitters: 6
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:7870860
OMIM Allelic Variant: 602568.0003
Last Evaluated: Jan 30, 2018
Review Status: reviewed by expert panel
Number of Submitters: 6
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:7870860
OMIM Allelic Variant: 602568.0003
Last Evaluated: Jan 30, 2018
Review Status: reviewed by expert panel
Number of Submitters: 6
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:7870860
OMIM Allelic Variant: 602568.0003
Last Evaluated: Jan 30, 2018
Review Status: reviewed by expert panel
Number of Submitters: 6
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:7870860
OMIM Allelic Variant: 602568.0003
Last Evaluated: Jan 30, 2018
Review Status: reviewed by expert panel
Number of Submitters: 6
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:7870860
OMIM Allelic Variant: 602568.0003
Last Evaluated: Jan 30, 2018
Review Status: reviewed by expert panel
Number of Submitters: 6
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:7870860
OMIM Allelic Variant: 602568.0003
Low clinical importance, Likely pathogenic — This common variant (HapMap allele frequency of 31.3%) in a protein involved in folate (B9) and cobalamin (B12) metabolism and is often reported as "MTRR I22M" (an alternative transcript position). Mothers homozygous for this variant are associated with having around a increased chance of a child with Down syndrome (risk of 0.4%, average risk in population is 0.25%). Notably, age plays a far larger role in the rate of Down syndrome (risk is 4.5% for a mother 45-years-of-age), and it is unknown how this variant may combine with the effect of age. There are conflicting reports associating this variant with incidence of neural tube defects, possibly when combined with MTHFR A222V.
Expert Reviewed drug response
Hetero
Gene:
UGT2B15
Variant:
c.253T>G
(p.Tyr85Asp)
rsID: rs1902023
Ref Allele: A
Alt Allele: C
Freq: 52.3358%
CADD: 0.027
ClinVar Submissions (1)
Last Evaluated: Dec 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 4:68670366
Last Evaluated: Dec 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 4:68670366
Expert Reviewed drug response
Hetero
Gene:
CYP4F2
Variant:
c.1297G>A
(p.Val433Met)
rsID: rs2108622
Ref Allele: C
Alt Allele: T
Freq: 22.5551%
CADD: 24.8
ClinVar Submissions (1)
Last Evaluated: Apr 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:15879621
Last Evaluated: Apr 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:15879621
Last Evaluated: Apr 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:15879621
Last Evaluated: Apr 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:15879621
Insufficiently evaluated pharmacogenetic — Requires 1mg/day greater dose of warfarin.
Expert Reviewed drug response
Hetero
Gene:
VDR
Variant:
c.2T>C
(p.Met1Thr)
rsID: rs2228570
Ref Allele: A
Alt Allele: G
Freq: 65.9746%
CADD: 24.6
ClinVar Submissions (3)
Last Evaluated: Mar 01, 2017
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 12:47879112
Last Evaluated: Mar 01, 2017
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 12:47879112
Last Evaluated: Mar 01, 2017
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 12:47879112
Expert Reviewed drug response
Homo
Gene:
HAS3
Variant:
c.279A>G
(p.Ala93=)
rsID: rs2232228
Ref Allele: A
Alt Allele: G
Freq: 33.7801%
CADD: 13.71
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:69109674
Expert Reviewed drug response
Hetero
Gene:
CYP2B6
Variant:
c.785A>G
(p.Lys262Arg)
rsID: rs2279343
Ref Allele: A
Alt Allele: G
Freq: 30.1836%
CADD: 5.035
ClinVar Submissions (4)
Highly active antiretroviral therapy (HAART) has reduced mortality associated with acquired immunodeficiency syndrome (AIDS; see 609423) by at least 70%. Efavirenz is a non-nucleoside reverse transcriptase inhibitor that is frequently prescribed with 2 nucleoside reverse transcriptase inhibitors as initial therapy for human immunodeficiency virus (HIV) infection. However, during the first weeks of therapy, up to half of patients who receive efavirenz experience CNS side effects, including dizziness, insomnia, impaired concentration, somnolence, and abnormal dreams. Severe depression, aggressive behavior, and paranoid or manic reactions may also occur, and such side effects may reflect varying efavirenz plasma concentrations. Plasma clearance of efavirenz appears slower in African Americans than in European Americans, and studies have suggested earlier virologic failure on efavirenz for both African Americans and Hispanics compared with European Americans. Efavirenz is metabolized primarily by hepatic CYP2B6, with some involvement of CYP3A (CYP3A4; 124010) (summary by Haas et al., 2004).
Last Evaluated: Mar 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:41009358
OMIM Allelic Variant: 123930.0002
Last Evaluated: Mar 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:41009358
OMIM Allelic Variant: 123930.0002
Expert Reviewed drug response
Hetero
Gene:
CYP2B6
Variant:
c.823-197T>C
rsID: rs2279345
Ref Allele: T
Alt Allele: C
Freq: 67.6653%
CADD: 1.711
ClinVar Submissions (1)
Last Evaluated: Dec 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:41009797
Expert Reviewed drug response
Hetero
Gene:
FDPS
Variant:
c.-1-98T>G
rsID: rs2297480
Ref Allele: T
Alt Allele: G
Freq: 30.5492%
CADD: 4.553
ClinVar Submissions (1)
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:155309691
Expert Reviewed drug response
Hetero
Gene:
ADORA2A
Variant:
c.-275+1797C>T
rsID: rs2298383
Ref Allele: C
Alt Allele: T
Freq: 47.8283%
CADD: 0.205
ClinVar Submissions (1)
Last Evaluated: Dec 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:24429543
Expert Reviewed drug response
Homo
Gene:
CYP3A4
Variant:
c.-392G>A
rsID: rs2740574
Ref Allele: C
Alt Allele: T
Freq: 77.7308%
CADD: 3.399
ClinVar Submissions (2)
Last Evaluated: Feb 23, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:99784473
OMIM Allelic Variant: 124010.0001
Last Evaluated: Feb 23, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:99784473
OMIM Allelic Variant: 124010.0001
Last Evaluated: Feb 23, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:99784473
OMIM Allelic Variant: 124010.0001
Expert Reviewed drug response
Homo
Gene:
-
Variant:
g.207629510T>C
rsID: rs2952768
Ref Allele: T
Alt Allele: C
Freq: 34.9683%
CADD: 6.283
ClinVar Submissions (1)
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:207629510
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:207629510
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:207629510
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:207629510
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:207629510
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:207629510
Expert Reviewed drug response
Hetero
Gene:
CYP2B6
Variant:
c.516G>T
(p.Gln172His)
rsID: rs3745274
Ref Allele: G
Alt Allele: T
Freq: 28.3121%
CADD: 0.01
ClinVar Submissions (2)
Highly active antiretroviral therapy (HAART) has reduced mortality associated with acquired immunodeficiency syndrome (AIDS; see 609423) by at least 70%. Efavirenz is a non-nucleoside reverse transcriptase inhibitor that is frequently prescribed with 2 nucleoside reverse transcriptase inhibitors as initial therapy for human immunodeficiency virus (HIV) infection. However, during the first weeks of therapy, up to half of patients who receive efavirenz experience CNS side effects, including dizziness, insomnia, impaired concentration, somnolence, and abnormal dreams. Severe depression, aggressive behavior, and paranoid or manic reactions may also occur, and such side effects may reflect varying efavirenz plasma concentrations. Plasma clearance of efavirenz appears slower in African Americans than in European Americans, and studies have suggested earlier virologic failure on efavirenz for both African Americans and Hispanics compared with European Americans. Efavirenz is metabolized primarily by hepatic CYP2B6, with some involvement of CYP3A (CYP3A4; 124010) (summary by Haas et al., 2004).
Last Evaluated: Apr 26, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:41006936
OMIM Allelic Variant: 123930.0001
Last Evaluated: Apr 26, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:41006936
OMIM Allelic Variant: 123930.0001
Last Evaluated: Apr 26, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:41006936
OMIM Allelic Variant: 123930.0001
Last Evaluated: Apr 26, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:41006936
OMIM Allelic Variant: 123930.0001
Last Evaluated: Apr 26, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:41006936
OMIM Allelic Variant: 123930.0001
Expert Reviewed drug response
Hetero
Gene:
PTGFR
Variant:
c.-562T>C
rsID: rs3753380
Ref Allele: T
Alt Allele: C
Freq: 78.9891%
CADD: 6.726
ClinVar Submissions (1)
Last Evaluated: Jan 21, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:78490747
Expert Reviewed drug response
Homo
Gene:
NEDD4L
Variant:
c.24G>A
(p.Gln8=)
rsID: rs4149601
Ref Allele: G
Alt Allele: A
Freq: 32.3896%
CADD: 6.379
ClinVar Submissions (1)
Last Evaluated: Apr 07, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:58149559
Last Evaluated: Apr 07, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:58149559
Expert Reviewed drug response
Hetero
Gene:
CYP2C19
Variant:
c.681G>A
(p.Pro227=)
rsID: rs4244285
Ref Allele: G
Alt Allele: A
Freq: 16.7312%
CADD: 2.285
ClinVar Submissions (4)
Clopidogrel is a thienopyridine antiplatelet agent that prevents platelet activation and aggregation by irreversibly inhibiting the P2Y12 ADP receptors. As a pro-drug, clopidogrel requires hepatic biotransformation to form an active metabolite. This conversion is composed of two sequential oxidative steps, which involve cytochrome P450-2C19 (CYP2C19) and other enzymes. Genetic variants in CYP2C19 such as CYP2C19*2, along with other genetic and non-genetic factors, are known to influence variability in clopidogrel response. Specific CYP2C19 variants impair formation of the active clopidogrel metabolite, which results in reduced platelet inhibition. Among clopidogrel-treated patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention (PCI), patients with specific variants in the CYP2C19 gene might be at increased risk for serious adverse cardiovascular events and may benefit from an alternative antiplatelet therapy as compared to patients without these variants. Guidelines regarding the use of pharmacogenomic tests in dosing for clopidogrel have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the PharmGKB website.
Last Evaluated: Aug 07, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:94781859
OMIM Allelic Variant: 124020.0001
Last Evaluated: Aug 07, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:94781859
OMIM Allelic Variant: 124020.0001
Last Evaluated: Aug 07, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:94781859
OMIM Allelic Variant: 124020.0001
Last Evaluated: Aug 07, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:94781859
OMIM Allelic Variant: 124020.0001
Last Evaluated: Aug 07, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:94781859
OMIM Allelic Variant: 124020.0001
Last Evaluated: Aug 07, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:94781859
OMIM Allelic Variant: 124020.0001
Last Evaluated: Aug 07, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:94781859
OMIM Allelic Variant: 124020.0001
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 07, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:94781859
OMIM Allelic Variant: 124020.0001
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 07, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:94781859
OMIM Allelic Variant: 124020.0001
Insufficiently evaluated pharmacogenetic — This variant defines the CYP2C19*2 haplotype and is associated with diminished response of clopidogrel (plavix). Compared to individuals who do not have this variant, carriers of this variant are more likely to have a major adverse cardiovascular event despite treatment with clopidogrel.
Expert Reviewed drug response
Hetero
Gene:
EGF
Variant:
c.-382A>G
rsID: rs4444903
Ref Allele: A
Alt Allele: G
Freq: 52.4321%
CADD: 8.542
ClinVar Submissions (2)
Last Evaluated: Feb 01, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 4:109912954
Last Evaluated: Feb 01, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 4:109912954
Expert Reviewed drug response
Hetero
Gene:
COQ2
Variant:
c.779-1022C>G
rsID: rs4693075
Ref Allele: G
Alt Allele: C
Freq: 61.6184%
CADD: 1.96
ClinVar Submissions (1)
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 4:83271015
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 4:83271015
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 4:83271015
Expert Reviewed drug response
Hetero
Gene:
FKBP5
Variant:
c.-20+18122T>C
rsID: rs4713916
Ref Allele: A
Alt Allele: G
Freq: 77.1709%
CADD: 0.798
ClinVar Submissions (1)
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:35702206
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:35702206
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:35702206
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:35702206
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:35702206
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:35702206
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:35702206
Expert Reviewed drug response
Homo
Gene:
CYP2C9
Variant:
c.820-6326A>C
rsID: rs4917639
Ref Allele: A
Alt Allele: C
Freq: 18.8209%
CADD: 1.887
ClinVar Submissions (1)
Last Evaluated: Feb 24, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:94965778
Expert Reviewed drug response
Hetero
Gene:
TANC1
Variant:
c.-15-22495C>T
rsID: rs6432512
Ref Allele: C
Alt Allele: T
Freq: 12.8958%
CADD: 0.018
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:159043401
Expert Reviewed drug response
Hetero
Gene:
DPP6
Variant:
c.52-71279T>C
rsID: rs6977820
Ref Allele: T
Alt Allele: C
Freq: 58.4257%
CADD: 6.496
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:154374935
Expert Reviewed drug response
Hetero
Gene:
TANC1
Variant:
c.-15-22919G>T
rsID: rs7582141
Ref Allele: G
Alt Allele: T
Freq: 12.6203%
CADD: 11.27
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:159042977
Expert Reviewed drug response
Hetero
Gene:
CRHR2
Variant:
c.-166-546T>A
rsID: rs7793837
Ref Allele: A
Alt Allele: T
Freq: 40.9069%
CADD: 2.37
ClinVar Submissions (1)
Last Evaluated: Jul 05, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:30687161
Last Evaluated: Jul 05, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:30687161
Expert Reviewed drug response
Hetero
Gene:
SLC28A3
Variant:
c.1381C>T
(p.Leu461=)
rsID: rs7853758
Ref Allele: G
Alt Allele: A
Freq: 19.716%
CADD: 17.57
ClinVar Submissions (1)
Last Evaluated: Dec 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 9:84286011
Expert Reviewed drug response
Hetero
Gene:
TCF7L2
Variant:
c.382-41435C>T
rsID: rs7903146
Ref Allele: C
Alt Allele: T
Freq: 27.0921%
CADD: 3.637
ClinVar Submissions (2)
Type 2 diabetes is a disorder characterized by abnormally high blood sugar levels. In this form of diabetes, the body stops using and making insulin properly. Insulin is a hormone produced in the pancreas that helps regulate blood sugar levels. Specifically, insulin controls how much glucose (a type of sugar) is passed from the blood into cells, where it is used as an energy source. When blood sugar levels are high (such as after a meal), the pancreas releases insulin to move the excess glucose into cells, which reduces the amount of glucose in the blood.Most people who develop type 2 diabetes first have insulin resistance, a condition in which the body's cells use insulin less efficiently than normal. As insulin resistance develops, more and more insulin is needed to keep blood sugar levels in the normal range. To keep up with the increasing need, insulin-producing cells in the pancreas (called beta cells) make larger amounts of insulin. Over time, the beta cells become less able to respond to blood sugar changes, leading to an insulin shortage that prevents the body from reducing blood sugar levels effectively. Most people have some insulin resistance as they age, but inadequate exercise and excessive weight gain make it worse, greatly increasing the likelihood of developing type 2 diabetes.Type 2 diabetes can occur at any age, but it most commonly begins in middle age or later. Signs and symptoms develop slowly over years. They include frequent urination (polyuria), excessive thirst (polydipsia), fatigue, blurred vision, tingling or loss of feeling in the hands and feet (diabetic neuropathy), sores that do not heal well, and weight loss. If blood sugar levels are not controlled through medication or diet, type 2 diabetes can cause long-lasting (chronic) health problems including heart disease and stroke; nerve damage; and damage to the kidneys, eyes, and other parts of the body.
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:112998590
OMIM Allelic Variant: 602228.0001
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:112998590
OMIM Allelic Variant: 602228.0001
Insufficiently evaluated pathogenic — associated with colorectal cancer for the T allele.
Expert Reviewed drug response
Hetero
Gene:
HTR2A
Variant:
c.614-2211T>C
rsID: rs7997012
Ref Allele: A
Alt Allele: G
Freq: 71.3279%
CADD: 11.64
ClinVar Submissions (3)
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 13:46837850
OMIM Allelic Variant: 182135.0003
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 13:46837850
OMIM Allelic Variant: 182135.0003
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 13:46837850
OMIM Allelic Variant: 182135.0003
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 13:46837850
OMIM Allelic Variant: 182135.0003
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 13:46837850
OMIM Allelic Variant: 182135.0003
Expert Reviewed drug response
Homo
Gene:
VKORC1
Variant:
c.283+124G>C
rsID: rs8050894
Ref Allele: C
Alt Allele: G
Freq: 39.1159%
CADD: 1.82
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093188
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093188
Expert Reviewed drug response
Homo
Gene:
VKORC1
Variant:
c.174-136C>T
rsID: rs9934438
Ref Allele: G
Alt Allele: A
Freq: 33.6352%
CADD: 14.98
ClinVar Submissions (5)
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 5
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093557
OMIM Allelic Variant: 608547.0008
Warfarin is an oral anti-coagulant used world-wide to treat and prevent thrombotic disorders. While it is highly effective, it has a very narrow therapeutic index making it difficult to dose correctly. Genetic variants in both cytochrome P450-2C9 (CYP2C9) and vitamin K-epoxide reductase complex (VKORC1) enzymes, along with non-genetic factors, are known to affect warfarin dose variability. Patients with specific variants in the gene CYP2C9 (the primary warfarin-metabolizing enzyme), such as CYP2C9*2 and CYP2C9*3, may require a lower dose of warfarin as compared to patients without these variants. Patients with a specific variant in VKORC1 (the target enzyme of warfarin), known as -1639G>A or rs9923231, may require a lower warfarin dose as compared to patients who do not have this variant. The combination of CYP2C9 and VKORC1 genetic variants, along with clinical factors, can put some patients at risk for adverse events such as bleeding. Guidelines regarding the use of pharmacogenomic tests in dosing for warfarin have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the PharmGKB website.
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 5
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093557
OMIM Allelic Variant: 608547.0008
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 5
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093557
OMIM Allelic Variant: 608547.0008
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 5
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093557
OMIM Allelic Variant: 608547.0008
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 5
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093557
OMIM Allelic Variant: 608547.0008
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 5
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093557
OMIM Allelic Variant: 608547.0008
Insufficiently evaluated pharmacogenetic — gene VKORC1 SNP 1173 C>T is strongly associated with low warfarin dose requirement.
Expert Reviewed drug response
Homo
Gene:
TANC1
Variant:
c.-125-6169A>C
rsID: rs10497203
Ref Allele: A
Alt Allele: C
Freq: 7.4844%
CADD: 4.173
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:158994911
Expert Reviewed drug response
Hetero
Gene:
C11orf65
Variant:
c.175-5285G>T
rsID: rs11212617
Ref Allele: C
Alt Allele: A
Freq: 47.0924%
CADD: 2.33
ClinVar Submissions (1)
Last Evaluated: Nov 17, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:108412434
Expert Reviewed drug response
Hetero
Gene:
-
Variant:
g.94645745G>A
rsID: rs12777823
Ref Allele: G
Alt Allele: A
Freq: 19.157%
CADD: 1.903
ClinVar Submissions (1)
Last Evaluated: Mar 09, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:94645745
Expert Reviewed drug response
Hetero
Gene:
COMT;TXNRD2
Variant:
c.103+197G>A
rsID: rs13306278
Ref Allele: C
Alt Allele: T
Freq: 9.3591%
CADD: 8.327
ClinVar Submissions (1)
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:19941504
Expert Reviewed drug response
Hetero
Gene:
MC4R
Variant:
g.60183864T>C
rsID: rs17782313
Ref Allele: T
Alt Allele: C
Freq: 24.1128%
CADD: 3.5
ClinVar Submissions (1)
Last Evaluated: Sep 22, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:60183864
Expert Reviewed drug response
Homo
Below are mutations from ClinVar that were submitted as "clinically significant." Variants shown may or may not be truly clinically significant. The data presented has no guarantees of reporting accuracy. Heterozygous variants are reported as yellow and homozygous variants as red. A red or yellow variant does not necessarily mean one has or carries a condition or disease. This is for research and educational purposes only.
Gene:
KCND3
Variant:
c.1348C>T
(p.Leu450Phe)
rsID: rs150401343
Ref Allele: G
Alt Allele: A
Freq: 0.0056%rare
CADD: 22.3
ClinVar Submissions (6)
Brugada syndrome is characterized by cardiac conduction abnormalities (ST-segment abnormalities in leads V1-V3 on ECG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and the sudden unexpected nocturnal death syndrome (SUNDS), a typical presentation in individuals from Southeast Asia. Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome.
Last Evaluated: Feb 01, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:111780713
OMIM Allelic Variant: 605411.0005
Last Evaluated: Feb 01, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:111780713
OMIM Allelic Variant: 605411.0005
The hereditary ataxias are a group of genetic disorders characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs. In this GeneReview the hereditary ataxias are categorized by mode of inheritance and gene (or chromosome locus) in which pathogenic variants occur.
Last Evaluated: Feb 01, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:111780713
OMIM Allelic Variant: 605411.0005
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 01, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:111780713
OMIM Allelic Variant: 605411.0005
This individual has one copy of the genetic mutation, and because the condition(s) are autosomal dominant, they may manifest the condition rather than just being a carrier. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
FLG
Variant:
c.7031C>G
(p.Ser2344Ter)
rsID: rs372754256
Ref Allele: G
Alt Allele: C
Freq: 0.0072%rare
CADD: 36
ClinVar Submissions (2)
Diseases that are caused by genetic mutations present during embryo or fetal development, although they may be observed later in life. The mutations may be inherited from a parent's genome or they may be acquired in utero.
Last Evaluated: Nov 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 1:152307855
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Nov 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 1:152307855
The data does not specify whether the genetic variant is autosomal recessive or autosomal dominant. For a definitive determination, refer to resources such as OMIM.
Clinically Significant Pathogenic
Hetero
Gene:
KRT74
Variant:
c.821T>C
(p.Phe274Ser)
rsID: rs147962513
Ref Allele: A
Alt Allele: G
Freq: 0.0159%rare
CADD: 33
ClinVar Submissions (3)
Some ectodermal dysplasias are here classified as congenital disorders characterized by abnormal development in 2 or more ectodermal structures (hair, nails, teeth, and sweat glands) without other systemic findings. Ectodermal dysplasia of the hair/nail type is a rare congenital condition characterized by hypotrichosis and nail dystrophy without nonectodermal or other ectodermal manifestations.
Last Evaluated: Dec 06, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:52571381
OMIM Allelic Variant: 608248.0004
Some ectodermal dysplasias are here classified as congenital disorders characterized by abnormal development in 2 or more ectodermal structures (hair, nails, teeth, and sweat glands) without other systemic findings. Ectodermal dysplasia of the hair/nail type is a rare congenital condition characterized by hypotrichosis and nail dystrophy without nonectodermal or other ectodermal manifestations.
Last Evaluated: Dec 06, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:52571381
OMIM Allelic Variant: 608248.0004
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 06, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:52571381
OMIM Allelic Variant: 608248.0004
This individual has one copy of the genetic mutation, and depending on the condition, this mutation can act as either autosomal dominant or recessive. Thus, they might manifest one condition while being a carrier for another. However, it's important to conduct thorough research before drawing definitive conclusions.
Clinically Significant Benign
Hetero
Gene:
BLK
Variant:
c.713G>A
(p.Arg238Gln)
rsID: rs141865425
Ref Allele: G
Alt Allele: A
Freq: 0.262%rare
CADD: 28
ClinVar Submissions (4)
Maturity-onset diabetes of the young is an autosomal dominant form of diabetes typically occurring before 25 years of age and caused by primary insulin secretion defects. Despite its low prevalence, MODY is not a single entity but represents genetic, metabolic, and clinical heterogeneity (Vaxillaire and Froguel, 2008). Genetic Heterogeneity of MODY MODY1 (125850) is caused by heterozygous mutation in the hepatocyte nuclear factor-4-alpha gene (HNF4A; 600281) on chromosome 20. MODY2 (125851) is caused by heterozygous mutation in the glucokinase gene (GCK; 138079) on chromosome 7. MODY3 (600496) is caused by heterozygous mutation in the hepatocyte nuclear factor-1alpha gene (HNF1A; 142410) on chromosome 12q24.2. MODY4 (606392) is caused by heterozygous mutation in the pancreas/duodenum homeobox protein-1 gene (PDX1; 600733) on chromosome 13q12.1. MODY5 (137920) is caused by heterozygous mutation in the gene encoding hepatic transcription factor-2 (TCF2; 189907) on chromosome 17cen-q21.3. MODY6 (606394) is caused by heterozygous mutation in the NEUROD1 gene (601724) on chromosome 2q32. MODY7 (610508) is caused by heterozygous mutation in the KLF11 gene (603301) on chromosome 2p25. MODY8 (609812), or diabetes-pancreatic exocrine dysfunction syndrome, is caused by heterozygous mutation in the CEL gene (114840) on chromosome 9q34. MODY9 (612225) is caused by heterozygous mutation in the PAX4 gene (167413) on chromosome 7q32. MODY10 (613370) is caused by heterozygous mutation in the insulin gene (INS; 176730) on chromosome 11p15.5. MODY11 (613375) is caused by heterozygous mutation in the BLK gene (191305) on chromosome 8p23. MODY13 (616329) is caused by heterozygous mutation in the KCNJ11 gene (600937) on chromosome 11p15. MODY14 (616511) is caused by heterozygous mutation in the APPL1 gene (604299) on chromosome 3p14.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 8:11555425
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by production of autoantibodies against nuclear, cytoplasmic, and cell surface molecules that transcend organ-specific boundaries. Tissue deposition of antibodies or immune complexes induces inflammation and subsequent injury of multiple organs and finally results in clinical manifestations of SLE, including glomerulonephritis, dermatitis, thrombosis, vasculitis, seizures, and arthritis. Evidence strongly suggests the involvement of genetic components in SLE susceptibility (summary by Oishi et al., 2008). Genetic Heterogeneity of Systemic Lupus Erythematosus An autosomal recessive form of systemic lupus erythematosus (SLEB16; 614420) is caused by mutation in the DNASE1L3 gene (602244) on chromosome 3p14.3. See MAPPING and MOLECULAR GENETICS sections for a discussion of genetic heterogeneity of susceptibility to SLE.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 8:11555425
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 8:11555425
This individual has one copy of the genetic mutation, and because the condition(s) are autosomal dominant, they may manifest the condition rather than just being a carrier. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
ABCC6
Variant:
c.3883-24G>A
rsID: rs59513011
Ref Allele: C
Alt Allele: T
Freq: 0.528%rare
CADD: 0.343
ClinVar Submissions (1)
Pseudoxanthoma elasticum (PXE) is a systemic disorder that affects the elastic tissue of the skin, the eye, and the cardiovascular and gastrointestinal systems. Individuals most commonly present with papules in the skin and/or with angioid streaks of the retina found on routine eye examination or associated with retinal hemorrhage. Rarely, individuals may present with vascular signs and symptoms, such as gastrointestinal bleeding, angina, or intermittent claudication. The most frequent cause of morbidity and disability in PXE is reduced vision from macular hemorrhage and disciform scarring of the macula. Most affected individuals live a normal life span.
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 16:16155055
This individual has one copy of the genetic mutation, and because it's autosomal recessive, they are likely a carrier rather than manifesting the condition. Interpretation of carrier status should be backed by thorough research.
Clinically Significant Pathogenic
Hetero
Gene:
GLI2
Variant:
c.4558G>A
(p.Asp1520Asn)
rsID: rs114814747
Ref Allele: G
Alt Allele: A
Freq: 1.0759%uncommon
CADD: 32
ClinVar Submissions (6)
Last Evaluated: Oct 29, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:120990472
OMIM Allelic Variant: 165230.0007
Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having "microform" HPE.
Last Evaluated: Oct 29, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:120990472
OMIM Allelic Variant: 165230.0007
Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having "microform" HPE.
Last Evaluated: Oct 29, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:120990472
OMIM Allelic Variant: 165230.0007
Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having "microform" HPE.
Last Evaluated: Oct 29, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:120990472
OMIM Allelic Variant: 165230.0007
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 29, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:120990472
OMIM Allelic Variant: 165230.0007
This individual has one copy of the genetic mutation, and because the condition(s) are autosomal dominant, they may manifest the condition rather than just being a carrier. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
ABCC6
Variant:
c.473C>T
(p.Ala158Val)
rsID: rs2606921
Ref Allele: G
Alt Allele: A
Freq: 1.666%uncommon
CADD: 10.52
ClinVar Submissions (1)
Pseudoxanthoma elasticum (PXE) is a systemic disorder that affects the elastic tissue of the skin, the eye, and the cardiovascular and gastrointestinal systems. Individuals most commonly present with papules in the skin and/or with angioid streaks of the retina found on routine eye examination or associated with retinal hemorrhage. Rarely, individuals may present with vascular signs and symptoms, such as gastrointestinal bleeding, angina, or intermittent claudication. The most frequent cause of morbidity and disability in PXE is reduced vision from macular hemorrhage and disciform scarring of the macula. Most affected individuals live a normal life span.
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 16:16219555
This individual has one copy of the genetic mutation, and because it's autosomal recessive, they are likely a carrier rather than manifesting the condition. Interpretation of carrier status should be backed by thorough research.
Clinically Significant Pathogenic
Hetero
Gene:
FECH
Variant:
c.163G>T
(p.Gly55Cys)
rsID: rs3848519
Ref Allele: C
Alt Allele: A
Freq: 1.9742%uncommon
CADD: 14.57
ClinVar Submissions (3)
Erythropoietic protoporphyria (EPP) is characterized by cutaneous photosensitivity (usually beginning in infancy or childhood) that results in tingling, burning, pain, and itching within 30 minutes after exposure to sun or ultraviolet light and may be accompanied by swelling and redness. Symptoms (which may seem out of proportion to the visible skin lesions) may persist for hours or days after the initial phototoxic reaction. Photosensitivity remains for life. Multiple episodes of acute photosensitivity may lead to chronic changes of sun-exposed skin (lichenification, leathery pseudovesicles, grooving around the lips) and loss of lunulae of the nails. Approximately 20%-30% of individuals with EPP have some degree of liver dysfunction, which is typically mild with slight elevations of the liver enzymes. Up to 5% may develop more advanced liver disease which may be accompanied by motor neuropathy similar to that seen in the acute porphyrias.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57580104
OMIM Allelic Variant: 612386.0001
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57580104
OMIM Allelic Variant: 612386.0001
This individual has one copy of the genetic mutation, and because it's autosomal recessive, they are likely a carrier rather than manifesting the condition. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
CP
Variant:
c.1652C>T
(p.Thr551Ile)
rsID: rs61733458
Ref Allele: G
Alt Allele: A
Freq: 2.0913%uncommon
CADD: 26.1
ClinVar Submissions (7)
Aceruloplasminemia is characterized by iron accumulation in the brain and viscera. The clinical triad of retinal degeneration, diabetes mellitus (DM), and neurologic disease is seen in individuals ranging from age 30 years to older than 70 years. The neurologic findings of movement disorder (blepharospasm, grimacing, facial and neck dystonia, tremors, chorea) and ataxia (gait ataxia, dysarthria) correspond to regions of iron deposition in the brain. Individuals with aceruloplasminemia often present with anemia prior to onset of DM or obvious neurologic problems. Cognitive dysfunction including apathy and forgetfulness occurs in more than half of individuals with this condition.
Last Evaluated: Jul 27, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:149198428
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 27, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:149198428
This individual has one copy of the genetic mutation, and because it's autosomal recessive, they are likely a carrier rather than manifesting the condition. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
LPL
Variant:
c.106G>A
(p.Asp36Asn)
rsID: rs1801177
Ref Allele: G
Alt Allele: A
Freq: 2.3366%uncommon
CADD: 15.36
ClinVar Submissions (5)
An imbalance between myocardial functional requirements and the capacity of the CORONARY VESSELS to supply sufficient blood flow. It is a form of MYOCARDIAL ISCHEMIA (insufficient blood supply to the heart muscle) caused by a decreased capacity of the coronary vessels.
Last Evaluated: Jun 13, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 8:19948197
OMIM Allelic Variant: 609708.0035
APOE p.Leu167del is a rare genetic variant described in 38 cases in the literature with a range of clinical phenotypes. Three phenotypes can be associated with the APOE p.Leu167del variant: Inherited lipemic splenomegaly (also known as sea-blue histiocytosis) characterized by hypertriglyceridemia and splenomegaly. Variable manifestations include thrombocytopenia, liver function abnormalities, and cardiovascular disease. Autosomal dominant hypercholesterolemia (ADH) characterized by markedly elevated LDL cholesterol levels that leads to premature morbidity and mortality from atherosclerotic cardiovascular disease (ASCVD). Familial combined hyperlipidemia (FCHL) characterized by variable elevations of total cholesterol, triglycerides, or LDL cholesterol and a high risk of premature ASCVD. It has been suggested that the phenotype associated with the APOE p.Leu167del variant may depend on multiple factors, including sex, APOE genotype, control of hyperlipidemia, gene-gene interactions, gene-environment interactions, or perhaps epigenetic and other non-Mendelian effects.
Last Evaluated: Jun 13, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 8:19948197
OMIM Allelic Variant: 609708.0035
Familial lipoprotein lipase (LPL) deficiency usually presents in childhood and is characterized by very severe hypertriglyceridemia with episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. Clearance of chylomicrons from the plasma is impaired, causing triglycerides to accumulate in plasma and the plasma to have a milky (lactescent or lipemic) appearance. Symptoms usually resolve with restriction of total dietary fat to =20 g/day.
Last Evaluated: Jun 13, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 8:19948197
OMIM Allelic Variant: 609708.0035
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 13, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 8:19948197
OMIM Allelic Variant: 609708.0035
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 13, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 8:19948197
OMIM Allelic Variant: 609708.0035
This individual has one copy of the genetic mutation, and depending on the condition, this mutation can act as either autosomal dominant or recessive. Thus, they might manifest one condition while being a carrier for another. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
BTD
Variant:
c.1336G>C
(p.Asp446His)
rsID: rs13078881
Ref Allele: G
Alt Allele: C
Freq: 2.5667%uncommon
CADD: 23.3
ClinVar Submissions (15)
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
This individual has one copy of the genetic mutation, and because it's autosomal recessive, they are likely a carrier rather than manifesting the condition. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Low clinical importance, pathogenic — This variant is implicated in partial and profound biotinidase deficiency. Alone, this variant is estimated to have a 52% loss of enzymatic activity. This variant is often found with A171T, and together they are reported to cause profound deficiency. Notably there is a report of asymptomatic double-mutant adults, so symptoms may have variable penetrance. This variant is found compound heterozygously with more serious mutations in cases of partial biotinidase deficiency.
Expert Reviewed Clinically Significant Conflicting/Uncertain
Hetero
Gene:
C2
Variant:
c.954G>C
(p.Glu318Asp)
rsID: rs9332739
Ref Allele: G
Alt Allele: C
Freq: 3.0302%uncommon
CADD: 13.09
ClinVar Submissions (3)
Age-related macular degeneration is an eye disease that is a leading cause of vision loss in older people in developed countries. The vision loss usually becomes noticeable in a person's sixties or seventies and tends to worsen over time.Age-related macular degeneration mainly affects central vision, which is needed for detailed tasks such as reading, driving, and recognizing faces. The vision loss in this condition results from a gradual deterioration of light-sensing cells in the tissue at the back of the eye that detects light and color (the retina). Specifically, age-related macular degeneration affects a small area near the center of the retina, called the macula, which is responsible for central vision. Side (peripheral) vision and night vision are generally not affected, but reduced dim light (scotopic) vision often occurs in the early stages of the disease.Researchers have described two major types of age-related macular degeneration, known as the dry form and the wet form. The dry form is much more common, accounting for 85 to 90 percent of all cases of age-related macular degeneration. It is characterized by a buildup of yellowish deposits called drusen beneath the retina and vision loss that worsens slowly over time. The condition typically affects vision in both eyes, although vision loss often occurs in one eye before the other.The wet form of age-related macular degeneration is associated with severe vision loss that can worsen rapidly. This form of the condition is characterized by the growth of abnormal, fragile blood vessels underneath the macula. These vessels leak blood and fluid, which damages the macula and makes central vision appear blurry and distorted.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:31936027
OMIM Allelic Variant: 613927.0004
Complement component 2 deficiency is a disorder that causes the immune system to malfunction, resulting in a form of immunodeficiency. Immunodeficiencies are conditions in which the immune system is not able to protect the body effectively from foreign invaders such as bacteria and viruses. People with complement component 2 deficiency have a significantly increased risk of recurrent bacterial infections, specifically of the lungs (pneumonia), the membrane covering the brain and spinal cord (meningitis), and the blood (sepsis), which may be life-threatening. These infections most commonly occur in infancy and childhood and become less frequent in adolescence and adulthood.Complement component 2 deficiency is also associated with an increased risk of developing autoimmune disorders such as systemic lupus erythematosus (SLE) or vasculitis. Autoimmune disorders occur when the immune system malfunctions and attacks the body's tissues and organs. Between 10 and 20 percent of individuals with complement component 2 deficiency develop SLE. Females with complement component 2 deficiency are more likely to have SLE than affected males, but this is also true of SLE in the general population.The severity of complement component 2 deficiency varies widely. While some affected individuals experience recurrent infections and other immune system difficulties, others do not have any health problems related to the disorder.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:31936027
OMIM Allelic Variant: 613927.0004
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells of the macula lutea.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:31936027
OMIM Allelic Variant: 613927.0004
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:31936027
OMIM Allelic Variant: 613927.0004
The individual has two copies of the variant, which suggests they may manifest the associated condition or trait. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Clinically Significant Conflicting/Uncertain
Homo
Gene:
C2;CFB
Variant:
c.26T>A
(p.Leu9His)
rsID: rs4151667
Ref Allele: T
Alt Allele: A
Freq: 3.035%uncommon
CADD: 23.1
ClinVar Submissions (3)
Age-related macular degeneration is an eye disease that is a leading cause of vision loss in older people in developed countries. The vision loss usually becomes noticeable in a person's sixties or seventies and tends to worsen over time.Age-related macular degeneration mainly affects central vision, which is needed for detailed tasks such as reading, driving, and recognizing faces. The vision loss in this condition results from a gradual deterioration of light-sensing cells in the tissue at the back of the eye that detects light and color (the retina). Specifically, age-related macular degeneration affects a small area near the center of the retina, called the macula, which is responsible for central vision. Side (peripheral) vision and night vision are generally not affected, but reduced dim light (scotopic) vision often occurs in the early stages of the disease.Researchers have described two major types of age-related macular degeneration, known as the dry form and the wet form. The dry form is much more common, accounting for 85 to 90 percent of all cases of age-related macular degeneration. It is characterized by a buildup of yellowish deposits called drusen beneath the retina and vision loss that worsens slowly over time. The condition typically affects vision in both eyes, although vision loss often occurs in one eye before the other.The wet form of age-related macular degeneration is associated with severe vision loss that can worsen rapidly. This form of the condition is characterized by the growth of abnormal, fragile blood vessels underneath the macula. These vessels leak blood and fluid, which damages the macula and makes central vision appear blurry and distorted.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:31946247
OMIM Allelic Variant: 138470.0003
Hemolytic-uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia, and renal failure caused by platelet thrombi in the microcirculation of the kidney and other organs. The onset of atypical HUS (aHUS) ranges from the neonatal period to adulthood. Genetic aHUS accounts for an estimated 60% of all aHUS. Individuals with genetic aHUS frequently experience relapse even after complete recovery following the presenting episode; 60% of genetic aHUS progresses to end-stage renal disease (ESRD).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:31946247
OMIM Allelic Variant: 138470.0003
Complement component 2 deficiency is a disorder that causes the immune system to malfunction, resulting in a form of immunodeficiency. Immunodeficiencies are conditions in which the immune system is not able to protect the body effectively from foreign invaders such as bacteria and viruses. People with complement component 2 deficiency have a significantly increased risk of recurrent bacterial infections, specifically of the lungs (pneumonia), the membrane covering the brain and spinal cord (meningitis), and the blood (sepsis), which may be life-threatening. These infections most commonly occur in infancy and childhood and become less frequent in adolescence and adulthood.Complement component 2 deficiency is also associated with an increased risk of developing autoimmune disorders such as systemic lupus erythematosus (SLE) or vasculitis. Autoimmune disorders occur when the immune system malfunctions and attacks the body's tissues and organs. Between 10 and 20 percent of individuals with complement component 2 deficiency develop SLE. Females with complement component 2 deficiency are more likely to have SLE than affected males, but this is also true of SLE in the general population.The severity of complement component 2 deficiency varies widely. While some affected individuals experience recurrent infections and other immune system difficulties, others do not have any health problems related to the disorder.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:31946247
OMIM Allelic Variant: 138470.0003
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells of the macula lutea.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:31946247
OMIM Allelic Variant: 138470.0003
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:31946247
OMIM Allelic Variant: 138470.0003
The individual has two copies of the variant, which suggests they may manifest the associated condition or trait. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Low clinical importance, Uncertain protective — This variant typically occurs along with E318D, forming the H10 haplotype. This variant appears to be protective; it was associated with a significantly lower incidence of age-related macular degeneration in an American study (OR = 0.45).
Clinically Significant Conflicting/Uncertain
Homo
Gene:
MEFV
Variant:
c.442G>C
(p.Glu148Gln)
rsID: rs3743930
Ref Allele: C
Alt Allele: G
Freq: 3.4069%uncommon
CADD: 21.6
ClinVar Submissions (12)
Familial Mediterranean fever (FMF) is divided into two phenotypes: type 1 and type 2. FMF type 1 is characterized by recurrent short episodes of inflammation and serositis including fever, peritonitis, synovitis, pleuritis, and, rarely, pericarditis and meningitis. The symptoms and severity vary among affected individuals, sometimes even among members of the same family. Amyloidosis, which can lead to renal failure, is the most severe complication, if untreated. FMF type 2 is characterized by amyloidosis as the first clinical manifestation of FMF in an otherwise asymptomatic individual.
Last Evaluated: Dec 30, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 12
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 16:3254626
OMIM Allelic Variant: 608107.0005
Familial Mediterranean fever (FMF) is divided into two phenotypes: type 1 and type 2. FMF type 1 is characterized by recurrent short episodes of inflammation and serositis including fever, peritonitis, synovitis, pleuritis, and, rarely, pericarditis and meningitis. The symptoms and severity vary among affected individuals, sometimes even among members of the same family. Amyloidosis, which can lead to renal failure, is the most severe complication, if untreated. FMF type 2 is characterized by amyloidosis as the first clinical manifestation of FMF in an otherwise asymptomatic individual.
Last Evaluated: Dec 30, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 12
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 16:3254626
OMIM Allelic Variant: 608107.0005
Familial Mediterranean fever (FMF) is divided into two phenotypes: type 1 and type 2. FMF type 1 is characterized by recurrent short episodes of inflammation and serositis including fever, peritonitis, synovitis, pleuritis, and, rarely, pericarditis and meningitis. The symptoms and severity vary among affected individuals, sometimes even among members of the same family. Amyloidosis, which can lead to renal failure, is the most severe complication, if untreated. FMF type 2 is characterized by amyloidosis as the first clinical manifestation of FMF in an otherwise asymptomatic individual.
Last Evaluated: Dec 30, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 12
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 16:3254626
OMIM Allelic Variant: 608107.0005
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 30, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 12
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 16:3254626
OMIM Allelic Variant: 608107.0005
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 30, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 12
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 16:3254626
OMIM Allelic Variant: 608107.0005
The individual has two copies of the variant, which suggests they may manifest the associated condition or trait. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Moderate clinical importance, Uncertain pathogenic — Some reports believe this cause Familial Mediterranean Fever in a recessive manner with reduced penetrance (i.e. not all get the disease). However, these reports lack strong statistical significance; other studies argue the variant is not associated with the disease.
Clinically Significant Conflicting/Uncertain
Homo
Gene:
CLEC7A
Variant:
c.714T>G
(p.Tyr238Ter)
rsID: rs16910526
Ref Allele: A
Alt Allele: C
Freq: 5.5181%
CADD: 40
ClinVar Submissions (2)
Aspergillus species are ubiquitous in nature and cause a wide spectrum of diseases, including saprophytic colonization of existing cavities (aspergilloma), allergic asthma, hypersensitivity pneumonitis, allergic bronchopulmonary aspergillosis, and disseminated disease associated with high mortality rates in patients with hematologic malignancies and recipients of solid organs and stem cell transplantations. Immunocompetent and nonatopic individuals are relatively resistant to infection, and disease occurs in the setting of host damage. Association of persistent inflammation with intractable infection is common in nonneutropenic patients after hematopoietic stem cell transplantation, as well as in allergic fungal diseases. The pathophysiology underlying Aspergillus infection highlights the bipolar nature of the inflammatory process in infection, in which early inflammation prevents or limits infection, but an uncontrolled response may oppose disease eradication (summary by Cunha et al., 2010). For information on familial occurrence of allergic bronchopulmonary aspergillosis, see 103920.
Last Evaluated: Mar 29, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:10118488
OMIM Allelic Variant: 606264.0001
Familial candidiasis is an inherited tendency to develop infections caused by a type of fungus called Candida. Affected individuals typically have infections of the skin, the nails, and the moist lining of body cavities (mucous membranes). These infections are recurrent and persistent, which means they come back repeatedly and can last a long time. This pattern of infection is called chronic mucocutaneous candidiasis.Candida is commonly present on the skin and on the mucous membranes, and in most people usually causes no health problems. However, certain medications (such as antibiotics and corticosteroids) and other factors can lead to occasional overgrowth of Candida (candidiasis) in the mouth (where it is known as thrush) or in the vagina. These episodes, commonly called yeast infections, usually last only a short time before being cleared by a healthy immune system.Most people with familial candidiasis have chronic or recurrent yeast infections that begin in early childhood. Skin infections lead to a rash with crusty, thickened patches; when these patches occur on the scalp, they can cause loss of hair in the affected area (scarring alopecia). Candidiasis of the nails can result in thick, cracked, and discolored nails and swelling and redness of the surrounding skin. Thrush and gastrointestinal symptoms such as bloating, constipation, or diarrhea are common in affected individuals. Women with familial candidiasis can develop frequent vaginal yeast infections, and infants can have yeast infections on the skin that cause persistent diaper rash.Depending on the genetic change involved in this condition, some affected individuals are at risk for developing systemic candidiasis, a more severe condition in which the infection spreads through the bloodstream to various organs including the brain and the meninges, which are the membranes covering the brain and spinal cord. Systemic candidiasis can be life-threatening.Chronic or recurrent yeast infections can occur in people without familial candidiasis. Some individuals experience recurrent candidiasis as part of a general susceptibility to infections because their immune systems are impaired by a disease such as acquired immune deficiency syndrome (AIDS) or severe combined immunodeficiency (SCID), medications, or other factors. Other individuals have syndromes such as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) or autosomal dominant hyper-IgE syndrome (AD-HIES) that include a tendency to develop candidiasis along with other signs and symptoms affecting various organs and systems of the body.
Last Evaluated: Mar 29, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:10118488
OMIM Allelic Variant: 606264.0001
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 29, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:10118488
OMIM Allelic Variant: 606264.0001
This individual has one copy of the genetic mutation, and because it's autosomal recessive, they are likely a carrier rather than manifesting the condition. Interpretation of carrier status should be backed by thorough research.
Low clinical importance, Uncertain pathogenic — This variant has been found to impair homan mucosal antifungal defense and was implicated in vulvovaginal candidiasis and mucocutaneous infections in a Dutch family.
Clinically Significant Benign
Hetero
Gene:
GATA4
Variant:
c.997+200G>A
rsID: rs3729851
Ref Allele: G
Alt Allele: A
Freq: 9.0612%
CADD: 1.083
ClinVar Submissions (1)
Critical congenital heart disease (CCHD) is a term that refers to a group of serious heart defects that are present from birth. These abnormalities result from problems with the formation of one or more parts of the heart during the early stages of embryonic development. CCHD prevents the heart from pumping blood effectively or reduces the amount of oxygen in the blood. As a result, organs and tissues throughout the body do not receive enough oxygen, which can lead to organ damage and life-threatening complications. Individuals with CCHD usually require surgery soon after birth.Although babies with CCHD may appear healthy for the first few hours or days of life, signs and symptoms soon become apparent. These can include an abnormal heart sound during a heartbeat (heart murmur), rapid breathing (tachypnea), low blood pressure (hypotension), low levels of oxygen in the blood (hypoxemia), and a blue or purple tint to the skin caused by a shortage of oxygen (cyanosis). If untreated, CCHD can lead to shock, coma, and death. However, most people with CCHD now survive past infancy due to improvements in early detection, diagnosis, and treatment.Some people with treated CCHD have few related health problems later in life. However, long-term effects of CCHD can include delayed development and reduced stamina during exercise. Adults with these heart defects have an increased risk of abnormal heart rhythms, heart failure, sudden cardiac arrest, stroke, and premature death.Each of the heart defects associated with CCHD affects the flow of blood into, out of, or through the heart. Some of the heart defects involve structures within the heart itself, such as the two lower chambers of the heart (the ventricles) or the valves that control blood flow through the heart. Others affect the structure of the large blood vessels leading into and out of the heart (including the aorta and pulmonary artery). Still others involve a combination of these structural abnormalities.People with CCHD have one or more specific heart defects. The heart defects classified as CCHD include coarctation of the aorta, double-outlet right ventricle, D-transposition of the great arteries, Ebstein anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia with intact septum, single ventricle, total anomalous pulmonary venous connection, tetralogy of Fallot, tricuspid atresia, and truncus arteriosus.
Last Evaluated: Jan 07, 2017
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 8:11755333
The data does not specify whether the genetic variant is autosomal recessive or autosomal dominant. For a definitive determination, refer to resources such as OMIM.
Clinically Significant Pathogenic
Hetero
Gene:
MBL2
Variant:
c.161G>A
(p.Gly54Asp)
rsID: rs1800450
Ref Allele: C
Alt Allele: T
Freq: 11.4233%
CADD: 23.7
ClinVar Submissions (2)
Mannose-binding lectin (MBL) deficiency, defined as MBL protein level of less than 100 ng/ml, is present in about 5% of people of European descent and in about 10% of sub-Saharan Africans. Most MBL-deficient adults appear healthy, but low levels of MBL are associated with increased risk of infection in toddlers, in cancer patients undergoing chemotherapy, and in organ-transplant patients receiving immunosuppressive drugs, particularly recipients of liver transplants (review by Degn et al., 2011). MBL is a soluble molecule that can activate the lectin pathway of the complement system; deficiency may thus lead to defects in the complement system (summary by Garcia-Laorden et al., 2008). Genetic Heterogeneity of Lectin Complement Activation Pathway Defects See also LCAPD2 (613791), caused by variation in the MASP2 gene (605102) on chromosome 1p36, and LCAPD3 (613860), caused by variation in the FCN3 gene (604973) on chromosome 1p36.
Last Evaluated: Oct 01, 2004
Review Status: no assertion criteria provided
Number of Submitters: 2
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 10:52771475
OMIM Allelic Variant: 154545.0001
This individual has one copy of the genetic mutation, and because the condition(s) are autosomal dominant, they may manifest the condition rather than just being a carrier. However, it's important to conduct thorough research before drawing definitive conclusions.
Low clinical importance, Likely pathogenic — This variant is associated with mannose binding protein deficiency which leads to impaired complement system immune response to mannose-rich pathogens. Patients homozygous for this allele or compound heterozygous are likely to have increased susceptibility to infection, but Hellemann et al. report heterosis for intensive care outcomes in heterozygous subjects. The wild-type version of this gene is known as variant allele A, while this is called variant allele B. See R52C (variant D) and G57E (variant C).
Clinically Significant Pathogenic
Hetero
Gene:
GATA4
Variant:
c.1146+177C>T
rsID: rs12156163
Ref Allele: C
Alt Allele: T
Freq: 15.1655%
CADD: 0.009
ClinVar Submissions (1)
Critical congenital heart disease (CCHD) is a term that refers to a group of serious heart defects that are present from birth. These abnormalities result from problems with the formation of one or more parts of the heart during the early stages of embryonic development. CCHD prevents the heart from pumping blood effectively or reduces the amount of oxygen in the blood. As a result, organs and tissues throughout the body do not receive enough oxygen, which can lead to organ damage and life-threatening complications. Individuals with CCHD usually require surgery soon after birth.Although babies with CCHD may appear healthy for the first few hours or days of life, signs and symptoms soon become apparent. These can include an abnormal heart sound during a heartbeat (heart murmur), rapid breathing (tachypnea), low blood pressure (hypotension), low levels of oxygen in the blood (hypoxemia), and a blue or purple tint to the skin caused by a shortage of oxygen (cyanosis). If untreated, CCHD can lead to shock, coma, and death. However, most people with CCHD now survive past infancy due to improvements in early detection, diagnosis, and treatment.Some people with treated CCHD have few related health problems later in life. However, long-term effects of CCHD can include delayed development and reduced stamina during exercise. Adults with these heart defects have an increased risk of abnormal heart rhythms, heart failure, sudden cardiac arrest, stroke, and premature death.Each of the heart defects associated with CCHD affects the flow of blood into, out of, or through the heart. Some of the heart defects involve structures within the heart itself, such as the two lower chambers of the heart (the ventricles) or the valves that control blood flow through the heart. Others affect the structure of the large blood vessels leading into and out of the heart (including the aorta and pulmonary artery). Still others involve a combination of these structural abnormalities.People with CCHD have one or more specific heart defects. The heart defects classified as CCHD include coarctation of the aorta, double-outlet right ventricle, D-transposition of the great arteries, Ebstein anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia with intact septum, single ventricle, total anomalous pulmonary venous connection, tetralogy of Fallot, tricuspid atresia, and truncus arteriosus.
Last Evaluated: Jan 07, 2017
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 8:11757260
The individual has two copies of the variant, which suggests they may manifest the associated condition or trait. However, it's important to conduct thorough research before drawing definitive conclusions.
Clinically Significant Pathogenic
Homo
Gene:
PTPRJ
Variant:
c.827A>C
(p.Gln276Pro)
rsID: rs1566734
Ref Allele: A
Alt Allele: C
Freq: 15.4211%
CADD: 6.591
ClinVar Submissions (1)
Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, stomach, ovary, small bowel, hepatobiliary tract, urinary tract, brain, and skin. In individuals with Lynch syndrome the following lifetime risks for cancer are seen: CRC: 52%-82% (mean age at diagnosis 44-61 years). Endometrial cancer in females: 25%-60% (mean age at diagnosis 48-62 years). Gastric cancer: 6%-13% (mean age at diagnosis 56 years). Ovarian cancer: 4%-12% (mean age at diagnosis 42.5 years; ~30% are diagnosed < age 40 years). The risk for other Lynch syndrome-related cancers is lower, though substantially increased over general population rates.
Last Evaluated: Jul 01, 2002
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 11:48123823
OMIM Allelic Variant: 600925.0002
The data does not specify whether the genetic variant is autosomal recessive or autosomal dominant. For a definitive determination, refer to resources such as OMIM.
Insufficiently evaluated not reviewed — This variant is associated with susceptibility to various cancers.
Clinically Significant Pathogenic
Hetero
Gene:
GATA4
Variant:
c.*852G>A
rsID: rs804290
Ref Allele: G
Alt Allele: A
Freq: 15.5358%
CADD: 0.562
ClinVar Submissions (1)
Critical congenital heart disease (CCHD) is a term that refers to a group of serious heart defects that are present from birth. These abnormalities result from problems with the formation of one or more parts of the heart during the early stages of embryonic development. CCHD prevents the heart from pumping blood effectively or reduces the amount of oxygen in the blood. As a result, organs and tissues throughout the body do not receive enough oxygen, which can lead to organ damage and life-threatening complications. Individuals with CCHD usually require surgery soon after birth.Although babies with CCHD may appear healthy for the first few hours or days of life, signs and symptoms soon become apparent. These can include an abnormal heart sound during a heartbeat (heart murmur), rapid breathing (tachypnea), low blood pressure (hypotension), low levels of oxygen in the blood (hypoxemia), and a blue or purple tint to the skin caused by a shortage of oxygen (cyanosis). If untreated, CCHD can lead to shock, coma, and death. However, most people with CCHD now survive past infancy due to improvements in early detection, diagnosis, and treatment.Some people with treated CCHD have few related health problems later in life. However, long-term effects of CCHD can include delayed development and reduced stamina during exercise. Adults with these heart defects have an increased risk of abnormal heart rhythms, heart failure, sudden cardiac arrest, stroke, and premature death.Each of the heart defects associated with CCHD affects the flow of blood into, out of, or through the heart. Some of the heart defects involve structures within the heart itself, such as the two lower chambers of the heart (the ventricles) or the valves that control blood flow through the heart. Others affect the structure of the large blood vessels leading into and out of the heart (including the aorta and pulmonary artery). Still others involve a combination of these structural abnormalities.People with CCHD have one or more specific heart defects. The heart defects classified as CCHD include coarctation of the aorta, double-outlet right ventricle, D-transposition of the great arteries, Ebstein anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia with intact septum, single ventricle, total anomalous pulmonary venous connection, tetralogy of Fallot, tricuspid atresia, and truncus arteriosus.
Last Evaluated: Jan 07, 2017
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 8:11759327
The individual has two copies of the variant, which suggests they may manifest the associated condition or trait. However, it's important to conduct thorough research before drawing definitive conclusions.
Clinically Significant Pathogenic
Homo
Gene:
-
Variant:
g.135105435A>G
rsID: rs4895441
Ref Allele: A
Alt Allele: G
Freq: 20.8501%
CADD: 1.571
ClinVar Submissions (1)
Fetal hemoglobin (HbF) levels vary considerably in healthy normal adults. The distribution of HbF and F cells, erythrocytes that contain measurable HbF, in healthy adults is continuous, although most adults have HbF of less than 0.6% of total Hb. Approximately 10 to 15% of individuals have increases of HbF ranging from 0.8% to 5%, a trait often referred to as hereditary persistence of fetal hemoglobin (HPFH), usually distributed unevenly among red cells. When coinherited with beta-thalassemia (see 613985) or sickle cell anemia (603903), HPFH can increase HbF output to levels that are clinically beneficial (Thein et al., 2007). For a general phenotypic description and a discussion of loci that may affect fetal hemoglobin levels, see HBFQTL1 (141749).
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely pathogenic
Assembly: GRCh38
Chromosome/Position: 6:135105435
This individual has one copy of the genetic mutation, and because the condition(s) are autosomal dominant, they may manifest the condition rather than just being a carrier. However, it's important to conduct thorough research before drawing definitive conclusions.
Clinically Significant Likely pathogenic
Hetero
Gene:
IRGM
Variant:
c.313C>T
(p.Leu105=)
rsID: rs10065172
Ref Allele: C
Alt Allele: T
Freq: 22.3974%
CADD: 2.631
ClinVar Submissions (1)
Last Evaluated: Jan 13, 2013
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 5:150848436
OMIM Allelic Variant: 608212.0001
The data does not specify whether the genetic variant is autosomal recessive or autosomal dominant. For a definitive determination, refer to resources such as OMIM.
Clinically Significant Pathogenic
Hetero
Gene:
ELAC2
Variant:
c.650C>T
(p.Ser217Leu)
rsID: rs4792311
Ref Allele: G
Alt Allele: A
Freq: 26.1938%
CADD: 13.71
ClinVar Submissions (3)
Prostate cancer is a common disease that affects men, usually in middle age or later. In this disorder, certain cells in the prostate become abnormal and multiply without control or order to form a tumor. The prostate is a gland that surrounds the male urethra and helps produce semen, the fluid that carries sperm.Early prostate cancer usually does not cause pain, and most affected men exhibit no noticeable symptoms. Men are often diagnosed as the result of health screenings, such as a blood test for a substance called prostate specific antigen (PSA) or a medical procedure called a digital rectal exam. As the tumor grows larger, signs and symptoms can include difficulty starting or stopping the flow of urine, a feeling of not being able to empty the bladder completely, blood in the urine or semen, or pain with ejaculation. However, these changes can also occur with many other genitourinary conditions. Having one or more of these symptoms does not necessarily mean that a man has prostate cancer.The severity and outcome of prostate cancer varies widely. Early-stage prostate cancer can usually be treated successfully, and some older men have prostate tumors that grow so slowly that they may never cause health problems during their lifetime, even without treatment. In other men, however, the cancer is much more aggressive; in these cases, prostate cancer can be life-threatening.Some cancerous tumors can invade surrounding tissue and spread to other parts of the body. Tumors that begin at one site and then spread to other areas of the body are called metastatic cancers. The signs and symptoms of metastatic cancer depend on where the disease has spread. If prostate cancer spreads, cancerous cells most often appear in the lymph nodes, bones, lungs, liver, or brain. Bone metastases of prostate cancer most often cause pain in the lower back, pelvis, or hips.A small percentage of all prostate cancers cluster in families. These hereditary cancers are associated with inherited gene mutations. Hereditary prostate cancers tend to develop earlier in life than non-inherited (sporadic) cases.
Last Evaluated: Feb 15, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:13011692
OMIM Allelic Variant: 605367.0001
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 15, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:13011692
OMIM Allelic Variant: 605367.0001
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 15, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:13011692
OMIM Allelic Variant: 605367.0001
The data does not specify whether the genetic variant is autosomal recessive or autosomal dominant. For a definitive determination, refer to resources such as OMIM.
Low clinical importance, Uncertain pathogenic — Reported to be associated with increased susceptibility to prostate cancer, but later studies weaken the hypothesis. Xu et al.'s meta-analysis concludes that there is a small but significant increased risk (OR = 1.13). Assuming a lifetime risk of 16% for prostate cancer we calculate this leads to an increased risk of ~1.5% (17.5% total).
Clinically Significant Benign
Hetero
Gene:
FGFR4
Variant:
c.1162G>A
(p.Gly388Arg)
rsID: rs351855
Ref Allele: G
Alt Allele: A
Freq: 26.6748%
CADD: 25.6
ClinVar Submissions (1)
Last Evaluated: Feb 01, 2002
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 5:177093242
OMIM Allelic Variant: 134935.0001
The data does not specify whether the genetic variant is autosomal recessive or autosomal dominant. For a definitive determination, refer to resources such as OMIM.
Insufficiently evaluated pharmacogenetic — Possible association with sensitivity to cisplatin; poor outcome with cyclophosphamide, fluoruracil, methotextrate and tamoxifen.
Clinically Significant Pathogenic
Hetero
Gene:
FECH
Variant:
c.68-23C>T
rsID: rs2269219
Ref Allele: G
Alt Allele: A
Freq: 27.9697%
CADD: 1.754
ClinVar Submissions (2)
Red discoloration of the skin caused by infectious agents, inflammation, drug hypersensitivity, or underlying disease.
Last Evaluated: Jan 25, 2016
Review Status: no assertion criteria provided
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57580222
OMIM Allelic Variant: 612386.0003
Erythropoietic protoporphyria (EPP) is characterized by cutaneous photosensitivity (usually beginning in infancy or childhood) that results in tingling, burning, pain, and itching within 30 minutes after exposure to sun or ultraviolet light and may be accompanied by swelling and redness. Symptoms (which may seem out of proportion to the visible skin lesions) may persist for hours or days after the initial phototoxic reaction. Photosensitivity remains for life. Multiple episodes of acute photosensitivity may lead to chronic changes of sun-exposed skin (lichenification, leathery pseudovesicles, grooving around the lips) and loss of lunulae of the nails. Approximately 20%-30% of individuals with EPP have some degree of liver dysfunction, which is typically mild with slight elevations of the liver enzymes. Up to 5% may develop more advanced liver disease which may be accompanied by motor neuropathy similar to that seen in the acute porphyrias.
Last Evaluated: Jan 25, 2016
Review Status: no assertion criteria provided
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57580222
OMIM Allelic Variant: 612386.0003
A clinical manifestation of HYPERBILIRUBINEMIA, characterized by the yellowish staining of the SKIN; MUCOUS MEMBRANE; and SCLERA. Clinical jaundice usually is a sign of LIVER dysfunction.
Last Evaluated: Jan 25, 2016
Review Status: no assertion criteria provided
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57580222
OMIM Allelic Variant: 612386.0003
This individual has one copy of the genetic mutation, and because it's autosomal recessive, they are likely a carrier rather than manifesting the condition. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
GUCY2D
Variant:
c.154G>T
(p.Ala52Ser)
rsID: rs61749665
Ref Allele: G
Alt Allele: T
Freq: 30.2171%
CADD: 5.656
ClinVar Submissions (5)
Leber congenital amaurosis is an eye disorder that primarily affects the retina, which is the specialized tissue at the back of the eye that detects light and color. People with this disorder typically have severe visual impairment beginning in infancy. The visual impairment tends to be stable, although it may worsen very slowly over time.Leber congenital amaurosis is also associated with other vision problems, including an increased sensitivity to light (photophobia), involuntary movements of the eyes (nystagmus), and extreme farsightedness (hyperopia). The pupils, which usually expand and contract in response to the amount of light entering the eye, do not react normally to light. Instead, they expand and contract more slowly than normal, or they may not respond to light at all. Additionally, the clear front covering of the eye (the cornea) may be cone-shaped and abnormally thin, a condition known as keratoconus.A specific behavior called Franceschetti's oculo-digital sign is characteristic of Leber congenital amaurosis. This sign consists of poking, pressing, and rubbing the eyes with a knuckle or finger. Researchers suspect that this behavior may contribute to deep-set eyes and keratoconus in affected children.In rare cases, delayed development and intellectual disability have been reported in people with the features of Leber congenital amaurosis. However, researchers are uncertain whether these individuals actually have Leber congenital amaurosis or another syndrome with similar signs and symptoms.At least 13 types of Leber congenital amaurosis have been described. The types are distinguished by their genetic cause, patterns of vision loss, and related eye abnormalities.
Last Evaluated: Dec 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:8003201
OMIM Allelic Variant: 600179.0004
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:8003201
OMIM Allelic Variant: 600179.0004
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:8003201
OMIM Allelic Variant: 600179.0004
The individual has two copies of the variant, which suggests they may manifest the associated condition or trait. However, it's important to conduct thorough research before drawing definitive conclusions.
Low clinical importance, Uncertain benign — One publication suggested that this variant possibly causes Leber's congenital amaurosis in a recessive manner, but the frequency data (36% in 1000 genomes) contradicts any significant pathogenic effect.
Clinically Significant Benign
Homo
Gene:
GCDH
Variant:
c.852+223C>T
rsID: rs11085825
Ref Allele: C
Alt Allele: T
Freq: 30.6846%
CADD: 1.467
ClinVar Submissions (1)
Glutaric acidemia I is an autosomal recessive metabolic disorder characterized by gliosis and neuronal loss in the basal ganglia and a progressive movement disorder that usually begins during the first year of life (Goodman et al., 1995). Hedlund et al. (2006) provided a detailed review of the clinical and biochemical aspects of glutaric acidemia type I.
Last Evaluated: Dec 08, 2015
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely pathogenic
Assembly: GRCh38
Chromosome/Position: 19:12896644
This individual has one copy of the genetic mutation, and because it's autosomal recessive, they are likely a carrier rather than manifesting the condition. Interpretation of carrier status should be backed by thorough research.
Clinically Significant Likely pathogenic
Hetero
Gene:
GCDH
Variant:
c.*288G>T
rsID: rs9384
Ref Allele: G
Alt Allele: T
Freq: 33.4719%
CADD: 1.464
ClinVar Submissions (2)
An increased concentration of glutaric acid in the blood.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:12899829
Glutaric acidemia I is an autosomal recessive metabolic disorder characterized by gliosis and neuronal loss in the basal ganglia and a progressive movement disorder that usually begins during the first year of life (Goodman et al., 1995). Hedlund et al. (2006) provided a detailed review of the clinical and biochemical aspects of glutaric acidemia type I.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:12899829
This individual has one copy of the genetic mutation, and because it's autosomal recessive, they are likely a carrier rather than manifesting the condition. Interpretation of carrier status should be backed by thorough research.
Clinically Significant Benign
Hetero
Gene:
CCDC170
Variant:
c.1810G>A
(p.Val604Ile)
rsID: rs6929137
Ref Allele: G
Alt Allele: A
Freq: 37.1743%
CADD: 4.328
ClinVar Submissions (1)
Estrogen resistance (ESTRR) is characterized by absence of puberty with elevated estradiol and gonadotropic hormones, as well as markedly delayed bone maturation. Female patients show absent breast development, small uterus, and enlarged multicystic ovaries; male patients may show small testes (Bernard et al., 2017). Some patients exhibit continued growth into adulthood (Smith et al., 1994).
Last Evaluated: Mar 01, 2014
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely pathogenic
Assembly: GRCh38
Chromosome/Position: 6:151615542
This individual has one copy of the genetic mutation, and because it's autosomal recessive, they are likely a carrier rather than manifesting the condition. Interpretation of carrier status should be backed by thorough research.
Clinically Significant Likely pathogenic
Hetero
Gene:
ACTN3
Variant:
c.1729C>T
(p.Arg577Ter)
rsID: rs1815739
Ref Allele: C
Alt Allele: T
Freq: 37.4841%
CADD: 40
ClinVar Submissions (1)
Last Evaluated: Oct 27, 2017
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Conflicting interpretations of pathogenicity, Affects
Assembly: GRCh38
Chromosome/Position: 11:66560624
OMIM Allelic Variant: 102574.0001
Last Evaluated: Oct 27, 2017
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Conflicting interpretations of pathogenicity, Affects
Assembly: GRCh38
Chromosome/Position: 11:66560624
OMIM Allelic Variant: 102574.0001
Last Evaluated: Oct 27, 2017
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Conflicting interpretations of pathogenicity, Affects
Assembly: GRCh38
Chromosome/Position: 11:66560624
OMIM Allelic Variant: 102574.0001
The data does not specify whether the genetic variant is autosomal recessive or autosomal dominant. For a definitive determination, refer to resources such as OMIM. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
GATA4
Variant:
c.1147-107A>G
rsID: rs745379
Ref Allele: A
Alt Allele: G
Freq: 38.0105%
CADD: 2.248
ClinVar Submissions (1)
Critical congenital heart disease (CCHD) is a term that refers to a group of serious heart defects that are present from birth. These abnormalities result from problems with the formation of one or more parts of the heart during the early stages of embryonic development. CCHD prevents the heart from pumping blood effectively or reduces the amount of oxygen in the blood. As a result, organs and tissues throughout the body do not receive enough oxygen, which can lead to organ damage and life-threatening complications. Individuals with CCHD usually require surgery soon after birth.Although babies with CCHD may appear healthy for the first few hours or days of life, signs and symptoms soon become apparent. These can include an abnormal heart sound during a heartbeat (heart murmur), rapid breathing (tachypnea), low blood pressure (hypotension), low levels of oxygen in the blood (hypoxemia), and a blue or purple tint to the skin caused by a shortage of oxygen (cyanosis). If untreated, CCHD can lead to shock, coma, and death. However, most people with CCHD now survive past infancy due to improvements in early detection, diagnosis, and treatment.Some people with treated CCHD have few related health problems later in life. However, long-term effects of CCHD can include delayed development and reduced stamina during exercise. Adults with these heart defects have an increased risk of abnormal heart rhythms, heart failure, sudden cardiac arrest, stroke, and premature death.Each of the heart defects associated with CCHD affects the flow of blood into, out of, or through the heart. Some of the heart defects involve structures within the heart itself, such as the two lower chambers of the heart (the ventricles) or the valves that control blood flow through the heart. Others affect the structure of the large blood vessels leading into and out of the heart (including the aorta and pulmonary artery). Still others involve a combination of these structural abnormalities.People with CCHD have one or more specific heart defects. The heart defects classified as CCHD include coarctation of the aorta, double-outlet right ventricle, D-transposition of the great arteries, Ebstein anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia with intact septum, single ventricle, total anomalous pulmonary venous connection, tetralogy of Fallot, tricuspid atresia, and truncus arteriosus.
Last Evaluated: Jan 07, 2017
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 8:11758186
The individual has two copies of the variant, which suggests they may manifest the associated condition or trait. However, it's important to conduct thorough research before drawing definitive conclusions.
Clinically Significant Pathogenic
Homo
Gene:
-
Variant:
g.198807802C>A
rsID: rs9660525
Ref Allele: C
Alt Allele: A
Freq: 38.3649%
CADD: 1.095
ClinVar Submissions (1)
An acute myeloid leukemia (AML) characterized by blasts with evidence of maturation to more mature neutrophils. (WHO, 2001)
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 1:198807802
The data does not specify whether the genetic variant is autosomal recessive or autosomal dominant. For a definitive determination, refer to resources such as OMIM.
Clinically Significant Pathogenic
Hetero
Gene:
UROS
Variant:
c.-219C>A
rsID: rs4385801
Ref Allele: G
Alt Allele: T
Freq: 40.7015%
CADD: 5.844
ClinVar Submissions (2)
Congenital erythropoietic porphyria (CEP) is characterized in most individuals by severe cutaneous photosensitivity with blistering and increased friability of the skin over light-exposed areas. Onset in most affected individuals occurs at birth or early infancy. The first manifestation is often pink to dark red discoloration of the urine. Hemolytic anemia is common and can range from mild to severe, with some affected individuals requiring chronic blood transfusions. Porphyrin deposition may lead to corneal ulcers and scarring, reddish-brown discoloration of the teeth (erythrodontia), and mild bone loss and/or expansion of the bone marrow. The phenotypic spectrum, however, is broad and ranges from non-immune hydrops fetalis in utero to late-onset disease with only mild cutaneous manifestations in adulthood.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:125823221
This individual has one copy of the genetic mutation, and because it's autosomal recessive, they are likely a carrier rather than manifesting the condition. Interpretation of carrier status should be backed by thorough research.
Clinically Significant Benign
Hetero
Gene:
PRSS1
Variant:
c.47C>T
(p.Ala16Val)
rsID: rs202003805
Ref Allele: C
Alt Allele: T
Freq: 40.938%
CADD: 0.048
ClinVar Submissions (6)
A disorder characterized by recurrent episodes of pancreatitis that start at a young age. It is caused by mutations in the PRSS1 or SPINK1 genes. Patients are at a high risk of developing pancreatic carcinoma.
Last Evaluated: Apr 15, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:142750561
A recurrent form of pancreatitis. [HPO:probinson]
Last Evaluated: Apr 15, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:142750561
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Apr 15, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:142750561
This individual has one copy of the genetic mutation, and because the condition(s) are autosomal dominant, they may manifest the condition rather than just being a carrier. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
CYP4V2
Variant:
c.64C>G
(p.Leu22Val)
rsID: rs1055138
Ref Allele: C
Alt Allele: G
Freq: 45.4383%
CADD: 3.733
ClinVar Submissions (6)
Bietti crystalline dystrophy (BCD) is a chorioretinal degeneration characterized by the presence of yellow-white crystals and/or complex lipid deposits in the retina and (to a variable degree) the cornea. Progressive atrophy and degeneration of the retinal pigment epithelium (RPE) / choroid lead to symptoms similar to those of other forms of retinal degeneration that fall under the category of retinitis pigmentosa and allied disorders, namely: reduced visual acuity, poor night vision, abnormal retinal electrophysiology, visual field loss, and often impaired color vision. Marked asymmetry between eyes is not uncommon. Onset is typically during the second to third decade of life, but ranges from the early teenage years to beyond the third decade. With time, loss of peripheral visual field, central acuity, or both result in legal blindness in most if not all affected individuals.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:186191887
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:186191887
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:186191887
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:186191887
This individual has one copy of the genetic mutation, and because it's autosomal recessive, they are likely a carrier rather than manifesting the condition. Interpretation of carrier status should be backed by thorough research.
Clinically Significant Benign
Hetero
Gene:
COL4A4
Variant:
c.3979G>A
(p.Val1327Met)
rsID: rs2229813
Ref Allele: C
Alt Allele: T
Freq: 46.2371%
CADD: 2.045
ClinVar Submissions (6)
Alport syndrome is a genetic condition characterized by kidney disease, hearing loss, and eye abnormalities.People with Alport syndrome experience progressive loss of kidney function. Almost all affected individuals have blood in their urine (hematuria), which indicates abnormal functioning of the kidneys. Many people with Alport syndrome also develop high levels of protein in their urine (proteinuria). The kidneys become less able to function as this condition progresses, resulting in end-stage renal disease (ESRD).People with Alport syndrome frequently develop sensorineural hearing loss, which is caused by abnormalities of the inner ear, during late childhood or early adolescence. Affected individuals may also have misshapen lenses in the eyes (anterior lenticonus) and abnormal coloration of the light-sensitive tissue at the back of the eye (retina). These eye abnormalities seldom lead to vision loss.Significant hearing loss, eye abnormalities, and progressive kidney disease are more common in males with Alport syndrome than in affected females.
Last Evaluated: May 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:227028004
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:227028004
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:227028004
The individual has two copies of the variant, which suggests they may manifest the associated condition or trait. However, it's important to conduct thorough research before drawing definitive conclusions.
Clinically Significant Benign
Homo
Gene:
MIR181A1HG
Variant:
n.364-18748G>A
rsID: rs12406470
Ref Allele: C
Alt Allele: T
Freq: 46.3358%
CADD: 2.063
ClinVar Submissions (1)
An acute myeloid leukemia (AML) characterized by blasts with evidence of maturation to more mature neutrophils. (WHO, 2001)
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 1:198826991
The data does not specify whether the genetic variant is autosomal recessive or autosomal dominant. For a definitive determination, refer to resources such as OMIM.
Clinically Significant Pathogenic
Hetero
Gene:
IL4R
Variant:
c.223A>G
(p.Ile75Val)
rsID: rs1805010
Ref Allele: A
Alt Allele: G
Freq: 46.8758%
CADD: 7.656
ClinVar Submissions (1)
Last Evaluated: May 14, 2015
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic, protective
Assembly: GRCh38
Chromosome/Position: 16:27344882
OMIM Allelic Variant: 147781.0002
Last Evaluated: May 14, 2015
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic, protective
Assembly: GRCh38
Chromosome/Position: 16:27344882
OMIM Allelic Variant: 147781.0002
The data does not specify whether the genetic variant is autosomal recessive or autosomal dominant. For a definitive determination, refer to resources such as OMIM.
Clinically Significant Pathogenic, protective
Hetero
Gene:
CCR5
Variant:
c.-301+246A>G
rsID: rs1799987
Ref Allele: A
Alt Allele: G
Freq: 49.3884%
CADD: 2.992
ClinVar Submissions (1)
Last Evaluated: Jul 08, 2003
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Conflicting interpretations of pathogenicity, protective
Assembly: GRCh38
Chromosome/Position: 3:46370444
OMIM Allelic Variant: 601373.0006
Last Evaluated: Jul 08, 2003
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Conflicting interpretations of pathogenicity, protective
Assembly: GRCh38
Chromosome/Position: 3:46370444
OMIM Allelic Variant: 601373.0006
Last Evaluated: Jul 08, 2003
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Conflicting interpretations of pathogenicity, protective
Assembly: GRCh38
Chromosome/Position: 3:46370444
OMIM Allelic Variant: 601373.0006
The data does not specify whether the genetic variant is autosomal recessive or autosomal dominant. For a definitive determination, refer to resources such as OMIM. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
MT-CYB
Variant:
m.14766C>T
rsID: rs193302980
Ref Allele: C
Alt Allele: T
ClinVar Submissions (1)
BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The exact cancer risks differ slightly depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant.
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely pathogenic
Assembly: GRCh38
Chromosome/Position: MT:14766
The individual has two copies of the variant, which suggests they may manifest the associated condition or trait. However, it's important to conduct thorough research before drawing definitive conclusions.
Clinically Significant Likely pathogenic
Homo
Gene:
MT-CYB
Variant:
m.15326A>G
rsID: rs2853508
Ref Allele: A
Alt Allele: G
ClinVar Submissions (1)
BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The exact cancer risks differ slightly depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant.
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely pathogenic
Assembly: GRCh38
Chromosome/Position: MT:15326
The individual has two copies of the variant, which suggests they may manifest the associated condition or trait. However, it's important to conduct thorough research before drawing definitive conclusions.
Clinically Significant Likely pathogenic
Homo
Gene:
MT-CYB
Variant:
m.15884G>A
rsID: rs527236195
Ref Allele: G
Alt Allele: A
ClinVar Submissions (1)
Ovarian cancer, the leading cause of death from gynecologic malignancy, is characterized by advanced presentation with loco-regional dissemination in the peritoneal cavity and the rare incidence of visceral metastases (Chi et al., 2001). These typical features relate to the biology of the disease, which is a principal determinant of outcome (Auersperg et al., 2001). Epithelial ovarian cancer is the most common form and encompasses 5 major histologic subtypes: papillary serous, endometrioid, mucinous, clear cell, and transitional cell. Epithelial ovarian cancer arises as a result of genetic alterations sustained by the ovarian surface epithelium (Stany et al., 2008; Soslow, 2008).
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely pathogenic
Assembly: GRCh38
Chromosome/Position: MT:15884
The individual has two copies of the variant, which suggests they may manifest the associated condition or trait. However, it's important to conduct thorough research before drawing definitive conclusions.
Clinically Significant Likely pathogenic
Homo
Gene:
MT-CYB
Variant:
m.15148G>A
rsID: rs527236206
Ref Allele: G
Alt Allele: A
ClinVar Submissions (1)
Ovarian cancer, the leading cause of death from gynecologic malignancy, is characterized by advanced presentation with loco-regional dissemination in the peritoneal cavity and the rare incidence of visceral metastases (Chi et al., 2001). These typical features relate to the biology of the disease, which is a principal determinant of outcome (Auersperg et al., 2001). Epithelial ovarian cancer is the most common form and encompasses 5 major histologic subtypes: papillary serous, endometrioid, mucinous, clear cell, and transitional cell. Epithelial ovarian cancer arises as a result of genetic alterations sustained by the ovarian surface epithelium (Stany et al., 2008; Soslow, 2008).
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely pathogenic
Assembly: GRCh38
Chromosome/Position: MT:15148
The individual has two copies of the variant, which suggests they may manifest the associated condition or trait. However, it's important to conduct thorough research before drawing definitive conclusions.
Clinically Significant Likely pathogenic
Homo
Below are rare variants (frequency less than 1%) that were submitted to ClinVar. The data presented has no guarantees of reporting accuracy. Heterozygous variants are reported as yellow and homozygous variants as red. A red or yellow variant does not necessarily mean one has or carries a condition or disease. This is for research and educational purposes only.
Gene:
PLEKHG5
Variant:
c.1535T>A
(p.Val512Asp)
rsID: rs548243654
Ref Allele: A
Alt Allele: T
Freq: 0.0008%rare
CADD: 20.5
ClinVar Submissions (1)
CMTRIC is an autosomal recessive peripheral neuropathy characterized by distal sensory impairment predominantly affecting the lower limbs and resulting in walking difficulties due to muscle weakness and atrophy. The upper limbs may also be affected. Electrophysiologic studies and sural nerve biopsy show mixed features of demyelinating and axonal neuropathy. The age at onset and the severity of the disease are variable (summary by Azzedine et al., 2013). For a discussion of genetic heterogeneity of autosomal recessive intermediate CMT, see CMTRIA (608340).
Last Evaluated: Jan 09, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:6470742
Last Evaluated: Jan 09, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:6470742
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
MCFD2
Variant:
c.*1289T>C
rsID: rs527427772
Ref Allele: A
Alt Allele: G
Freq: 0.0008%rare
CADD: 5.498
ClinVar Submissions (1)
Combined deficiency of factor V (612309) and factor VIII (300841) is characterized by bleeding symptoms similar to those in hemophilia (306700) or parahemophilia (227400), caused by single deficiency of FV or FVIII, respectively. The most common symptoms are epistaxis, menorrhagia, and excessive bleeding during or after trauma. Plasma FV and FVIII antigen and activity levels are in the range of 5 to 30%. Inheritance of F5F8D is autosomal recessive and distinct from the coinheritance of FV deficiency and FVIII deficiency (summary by Zhang and Ginsburg, 2004). Genetic Heterogeneity of Combined Deficiency of Factor V and Factor VIII Another form of combined deficiency of factor V and factor VII (F5F8D2; 613625) is caused by mutation in the MCFD2 gene (607788) on chromosome 2.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:46904174
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
PDE8B
Variant:
c.1921G>A
(p.Asp641Asn)
rsID: rs539447103
Ref Allele: G
Alt Allele: A
Freq: 0.0008%rare
CADD: 26.7
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:77418238
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
ARSB
Variant:
c.-276T>C
rsID: rs534158632
Ref Allele: A
Alt Allele: G
Freq: 0.0008%rare
CADD: 7.677
ClinVar Submissions (1)
Mucopolysaccharidosis type VI is an autosomal recessive lysosomal storage disorder resulting from a deficiency of arylsulfatase B. Clinical features and severity are variable, but usually include short stature, hepatosplenomegaly, dysostosis multiplex, stiff joints, corneal clouding, cardiac abnormalities, and facial dysmorphism. Intelligence is usually normal (Azevedo et al., 2004).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 5:78985524
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
RAB3GAP2
Variant:
c.*2043G>A
rsID: rs367962640
Ref Allele: C
Alt Allele: T
Freq: 0.0016%rare
CADD: 13.24
ClinVar Submissions (1)
RAB18 deficiency is the molecular deficit underlying both Warburg micro syndrome (characterized by eye, nervous system, and endocrine abnormalities) and Martsolf syndrome (characterized by similar – but milder – findings). To date Warburg micro syndrome comprises >96% of reported individuals with genetically defined RAB18 deficiency. The hallmark ophthalmologic findings are bilateral congenital cataracts, usually accompanied by microphthalmia, microcornea (diameter <10), and small atonic pupils. Poor vision despite early cataract surgery likely results from progressive optic atrophy and cortical visual impairment. Individuals with Warburg micro syndrome have severe to profound intellectual disability (ID); those with Martsolf syndrome have mild to moderate ID. Some individuals with RAB18 deficiency also have epilepsy. In Warburg micro syndrome, a progressive ascending spastic paraplegia typically begins with spastic diplegia and contractures during the first year, followed by upper limb involvement leading to spastic quadriplegia after about age five years, often eventually causing breathing difficulties. In Martsolf syndrome infantile hypotonia is followed primarily by slowly progressive lower limb spasticity. Hypogonadism – when present – manifests in both syndromes, in males as micropenis and/or cryptorchidism and in females as hypoplastic labia minora, clitoral hypoplasia, and small introitus.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:220149208
Warburg Micro syndrome is a rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism (summary by Morris-Rosendahl et al., 2010). Genetic Heterogeneity of Warburg Micro Syndrome Warburg Micro syndrome-2 (WARBM2; 614225) is caused by mutation in the RAB3GAP2 gene (609275) on chromosome 1q41. WARBM3 (614222) is caused by mutation in the RAB18 gene (602207) on chromosome 10p12. WARBM4 (615663) is caused by mutation in the TBC1D20 gene (611663) on chromosome 20p13. See also Martsolf syndrome (212720), a clinically overlapping but milder autosomal recessive disorder caused by autosomal recessive mutation in the RAB3GAP2 gene. Handley et al. (2013) provided an overview of the disease variants identified in the RAB3GAP1, RAB3GAP2, and RAB18 genes, noting that a total of 144 families with WARBM and 9 families with Martsolf syndrome had been studied. Mutations were identified in RAB3GAP1 in 41% of cases, in RAB3GAP2 in 7% of cases, and in RAB18 in 5% of cases. Although RAB18 had not been linked to RAB3 pathways, Handley et al. (2013) stated that mutations in all 3 genes cause an indistinguishable phenotype, making it likely that there is some functional overlap.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:220149208
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
SLC6A20
Variant:
c.*1506A>T
rsID: rs539802611
Ref Allele: T
Alt Allele: A
Freq: 0.0016%rare
CADD: 2.933
ClinVar Submissions (1)
The imino acids, proline and hydroxyproline, share a renal tubular reabsorptive mechanism with glycine. Iminoglycinuria (IG; 242600), a benign inborn error of amino acid transport, is also a normal finding in neonates and infants under 6 months of age (Chesney, 2001). Early studies of families with iminoglycinuria suggested genetic complexity, with homozygotes developing IG and heterozygotes manifesting only hyperglycinuria (HG) (summary by Broer et al., 2008). A phenotype of combined glucosuria and glycinuria has been described (see 138070).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 3:45757472
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
CTSD
Variant:
c.-53C>T
rsID: rs530324803
Ref Allele: G
Alt Allele: A
Freq: 0.0016%rare
CADD: 17.93
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 11:1763912
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
GRIP1
Variant:
c.*499A>G
rsID: rs572566894
Ref Allele: T
Alt Allele: C
Freq: 0.0016%rare
CADD: 14.69
ClinVar Submissions (1)
Fraser syndrome is an autosomal recessive malformation disorder characterized by cryptophthalmos, syndactyly, and abnormalities of the respiratory and urogenital tract (summary by van Haelst et al., 2008). Genetic Heterogeneity of Fraser Syndrome Fraser syndrome-2 (FRASRS2) is caused by mutation in the FREM2 gene (608945) on chromosome 13q13, and Fraser syndrome-3 (FRASRS3) is caused by mutation in the GRIP1 gene (604597) on chromosome 12q14. See Bowen syndrome (211200) for a comparable but probably distinct syndrome of multiple congenital malformations.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 12:66348520
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
GJB2
Variant:
c.71G>A
(p.Trp24Ter)
rsID: rs104894396
Ref Allele: C
Alt Allele: T
Freq: 0.0016%rare
CADD: 43
ClinVar Submissions (17)
DFNX2, also known as DFN3, is an X-linked recessive disorder characterized by progressive conductive and sensorineural hearing loss and a pathognomonic temporal bone deformity that includes dilatation of the inner auditory canal and a fistulous connection between the internal auditory canal and the cochlear basal turn, resulting in a perilymphatic fluid 'gusher' during stapes surgery (summary by de Kok et al., 1995 and Song et al., 2010). See also choroideremia, deafness, and mental retardation (303110), a contiguous gene deletion syndrome involving the POU3F4 and CHM (300390) genes on Xq21; isolated choroideremia (303100) is caused by mutation in the CHM gene.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
Nonsyndromic hearing loss and deafness, DFNA3 is characterized by pre- or postlingual, mild-to-profound progressive high-frequency sensorineural hearing impairment. Affected individuals have no other associated medical findings.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
Nonsyndromic hearing loss and deafness, DFNA3 is characterized by pre- or postlingual, mild-to-profound progressive high-frequency sensorineural hearing impairment. Affected individuals have no other associated medical findings.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
Nonsyndromic hearing loss and deafness (DFNB1) is characterized by congenital non-progressive mild-to-profound sensorineural hearing impairment. No other associated medical findings are present.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
Nonsyndromic hearing loss and deafness (DFNB1) is characterized by congenital non-progressive mild-to-profound sensorineural hearing impairment. No other associated medical findings are present.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
A decreased magnitude of the sensory perception of sound. [HPO:probinson]
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
A partial or complete loss of hearing in one or both ears. It is classified as conductive, sensory, or central.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
Hystrix-like ichthyosis with deafness (HID) is a disorder characterized by dry, scaly skin (ichthyosis) and hearing loss that is usually profound. Hystrix-like means resembling a porcupine; in this type of ichthyosis, the scales may be thick and spiky, giving the appearance of porcupine quills.Newborns with HID typically develop reddened skin. The skin abnormalities worsen over time, and the ichthyosis eventually covers most of the body, although the palms of the hands and soles of the feet are usually only mildly affected. Breaks in the skin may occur and in severe cases can lead to life-threatening infections. Affected individuals have an increased risk of developing a type of skin cancer called squamous cell carcinoma, which can also affect mucous membranes such as the inner lining of the mouth. People with HID may also have patchy hair loss caused by scarring on particular areas of skin.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
Palmoplantar keratoderma with deafness is a disorder characterized by skin abnormalities and hearing loss. Affected individuals develop unusually thick skin on the palms of the hands and soles of the feet (palmoplantar keratoderma) beginning in childhood. Hearing loss ranges from mild to profound. It begins in early childhood and gets worse over time. Affected individuals have particular trouble hearing high-pitched sounds.The signs and symptoms of this disorder may vary even within the same family, with some individuals developing only skin abnormalities and others developing only hearing loss.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
Bart-Pumphrey syndrome is characterized by nail and skin abnormalities and hearing loss.People with Bart-Pumphrey syndrome typically have a white discoloration of the nails (leukonychia); the nails may also be thick and crumbly. Affected individuals often have wart-like (verrucous) skin growths called knuckle pads on the knuckles of the fingers and toes. They may also have thickening of the skin on the palms of the hands and soles of the feet (palmoplantar keratoderma). The skin abnormalities generally become noticeable during childhood.The hearing loss associated with Bart-Pumphrey syndrome ranges from moderate to profound and is typically present from birth (congenital).The signs and symptoms of this disorder may vary even within the same family; while almost all affected individuals have hearing loss, they may have different combinations of the other associated features.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
Vohwinkel syndrome is a disorder with classic and variant forms, both of which affect the skin.In the classic form of Vohwinkel syndrome, affected individuals have thick, honeycomb-like calluses on the palms of the hands and soles of the feet (palmoplantar keratoses) beginning in infancy or early childhood. Affected children also typically have distinctive starfish-shaped patches of thickened skin on the tops of the fingers and toes or on the knees. Within a few years they develop tight bands of abnormal fibrous tissue around their fingers and toes (pseudoainhum); the bands may cut off the circulation to the digits and result in spontaneous amputation. People with the classic form of the disorder also have hearing loss.The variant form of Vohwinkel syndrome does not involve hearing loss, and the skin features also include widespread dry, scaly skin (ichthyosis), especially on the limbs. The ichthyosis is usually mild, and there may also be mild reddening of the skin (erythroderma). Some affected infants are born with a tight, clear sheath covering their skin called a collodion membrane. This membrane is usually shed during the first few weeks of life.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
Nonsyndromic hearing loss is a partial or total loss of hearing that is not associated with other signs and symptoms. In contrast, syndromic hearing loss occurs with signs and symptoms affecting other parts of the body.Nonsyndromic hearing loss can be classified in several different ways. One common way is by the condition's pattern of inheritance: autosomal dominant (DFNA), autosomal recessive (DFNB), X-linked (DFNX), or mitochondrial (which does not have a special designation). Each of these types of hearing loss includes multiple subtypes. DFNA, DFNB, and DFNX subtypes are numbered in the order in which they were first described. For example, DFNA1 was the first type of autosomal dominant nonsyndromic hearing loss to be identified.The characteristics of nonsyndromic hearing loss vary among the different types. Hearing loss can affect one ear (unilateral) or both ears (bilateral). Degrees of hearing loss range from mild (difficulty understanding soft speech) to profound (inability to hear even very loud noises). The term "deafness" is often used to describe severe-to-profound hearing loss. Hearing loss can be stable, or it may be progressive, becoming more severe as a person gets older. Particular types of nonsyndromic hearing loss show distinctive patterns of hearing loss. For example, the loss may be more pronounced at high, middle, or low tones.Most forms of nonsyndromic hearing loss are described as sensorineural, which means they are associated with a permanent loss of hearing caused by damage to structures in the inner ear. The inner ear processes sound and sends the information to the brain in the form of electrical nerve impulses. Less commonly, nonsyndromic hearing loss is described as conductive, meaning it results from changes in the middle ear. The middle ear contains three tiny bones that help transfer sound from the eardrum to the inner ear. Some forms of nonsyndromic hearing loss, particularly a type called DFNX2, involve changes in both the inner ear and the middle ear. This combination is called mixed hearing loss.Depending on the type, nonsyndromic hearing loss can become apparent at any time from infancy to old age. Hearing loss that is present before a child learns to speak is classified as prelingual or congenital. Hearing loss that occurs after the development of speech is classified as postlingual.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 17
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 13:20189511
OMIM Allelic Variant: 121011.0003
This individual has one copy of the genetic mutation, and depending on the condition, this mutation can act as either autosomal dominant or recessive. Thus, they might manifest one condition while being a carrier for another. However, it's important to conduct thorough research before drawing definitive conclusions.
Expert Reviewed Clinically Significant Pathogenic
Hetero
Gene:
BLM
Variant:
c.261G>A
(p.Lys87=)
rsID: rs372668612
Ref Allele: G
Alt Allele: A
Freq: 0.0016%rare
CADD: 1.45
ClinVar Submissions (3)
Bloom syndrome (BSyn) is characterized by severe pre- and postnatal growth deficiency, immune abnormalities, sensitivity to sunlight, insulin resistance, and a high risk for many cancers that occur at an early age. Despite their very small head circumference, most affected individuals have normal intellectual ability. Women may be fertile but often have early menopause, and men tend to be infertile, with only one confirmed case of paternity. Serious medical complications that are more common than in the general population and that also appear at unusually early ages include chronic obstructive pulmonary disease, diabetes mellitus as a result of insulin resistance, and cancer of a wide variety of types and anatomic sites.
Last Evaluated: Dec 19, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 15:90749529
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Dec 19, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 15:90749529
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 19, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 15:90749529
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
CDT1
Variant:
c.782G>A
(p.Gly261Asp)
rsID: rs755194747
Ref Allele: G
Alt Allele: A
Freq: 0.0016%rare
CADD: 21.5
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 27, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 16:88805819
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
FECH
Variant:
c.913-7C>T
rsID: rs369538477
Ref Allele: G
Alt Allele: A
Freq: 0.0016%rare
CADD: 3.008
ClinVar Submissions (1)
Erythropoietic protoporphyria (EPP) is characterized by cutaneous photosensitivity (usually beginning in infancy or childhood) that results in tingling, burning, pain, and itching within 30 minutes after exposure to sun or ultraviolet light and may be accompanied by swelling and redness. Symptoms (which may seem out of proportion to the visible skin lesions) may persist for hours or days after the initial phototoxic reaction. Photosensitivity remains for life. Multiple episodes of acute photosensitivity may lead to chronic changes of sun-exposed skin (lichenification, leathery pseudovesicles, grooving around the lips) and loss of lunulae of the nails. Approximately 20%-30% of individuals with EPP have some degree of liver dysfunction, which is typically mild with slight elevations of the liver enzymes. Up to 5% may develop more advanced liver disease which may be accompanied by motor neuropathy similar to that seen in the acute porphyrias.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 18:57554431
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
HMCN1
Variant:
c.710G>T
(p.Arg237Ile)
rsID: rs530178194
Ref Allele: G
Alt Allele: T
Freq: 0.0024%rare
CADD: 23.1
ClinVar Submissions (1)
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells of the macula lutea.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:185909425
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
ALMS1
Variant:
c.2820A>G
(p.Val940=)
rsID: rs376517753
Ref Allele: A
Alt Allele: G
Freq: 0.0024%rare
CADD: 1.108
ClinVar Submissions (1)
Alström syndrome is characterized by cone-rod dystrophy, obesity, progressive sensorineural hearing impairment, dilated or restrictive cardiomyopathy, the insulin resistance syndrome, and multiple organ failure. Wide clinical variability is observed among affected individuals, even within the same family. Cone-rod dystrophy presents as progressive visual impairment, photophobia, and nystagmus usually starting between birth and age 15 months. Many individuals lose all perception of light by the end of the second decade, but a minority retain the ability to read large print into the third decade. Children usually have normal birth weight but develop truncal obesity during their first year. Progressive sensorineural hearing loss presents in the first decade in as many as 70% of individuals. Hearing loss may progress to the severe or moderately severe range (40-70 db) by the end of the first to second decade. Insulin resistance is typically accompanied by the skin changes of acanthosis nigricans, and proceeds to type 2 diabetes in the majority by the third decade. Nearly all demonstrate associated dyslipidemia. Other endocrine abnormalities can include hypothyroidism, hypogonadotropic hypogonadism in boys, and polycystic ovaries in girls. More than 60% of individuals with Alström syndrome develop cardiac failure as a result of dilated or restrictive cardiomyopathy. About 50% of individuals have delay in early developmental milestones; intelligence is normal. Liver involvement includes elevation of transaminases, steatosis, hepatosplenomegaly, and steatohepatitis. Portal hypertension and cirrhosis can lead to hepatic encephalopathy and life-threatening esophageal varices. Pulmonary dysfunction and severe renal disease may also develop. End-stage renal disease (ESRD) can occur as early as the late teens.
Last Evaluated: Apr 20, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:73449344
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
IFT80
Variant:
c.282G>A
(p.Lys94=)
rsID: rs548358266
Ref Allele: C
Alt Allele: T
Freq: 0.0024%rare
CADD: 18.76
ClinVar Submissions (1)
Asphyxiating thoracic dystrophy, also known as Jeune syndrome, is an inherited disorder of bone growth characterized by a narrow chest, short ribs, shortened bones in the arms and legs, short stature, and extra fingers and toes (polydactyly). Additional skeletal abnormalities can include unusually shaped collarbones (clavicles) and pelvic bones, and and cone-shaped ends of the long bones in the arms and legs. Many infants with this condition are born with an extremely narrow, bell-shaped chest that can restrict the growth and expansion of the lungs. Life-threatening problems with breathing result, and people with asphyxiating thoracic dystrophy may live only into infancy or early childhood. However, in people who survive beyond the first few years, the narrow chest and related breathing problems can improve with age.Some people with asphyxiating thoracic dystrophy are born with less severe skeletal abnormalities and have only mild breathing difficulties, such as rapid breathing or shortness of breath. These individuals may live into adolescence or adulthood. After infancy, people with this condition may develop life-threatening kidney (renal) abnormalities that cause the kidneys to malfunction or fail. Heart defects and a narrowing of the airway (subglottic stenosis) are also possible. Other, less common features of asphyxiating thoracic dystrophy include liver disease, fluid-filled sacs (cysts) in the pancreas, dental abnormalities, and an eye disease called retinal dystrophy that can lead to vision loss.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 3:160377518
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
NSD2
Variant:
c.*1849C>T
rsID: rs562324621
Ref Allele: C
Alt Allele: T
Freq: 0.0024%rare
CADD: 0.247
ClinVar Submissions (1)
Wolf-Hirschhorn syndrome (WHS) is characterized by typical craniofacial features in infancy consisting of "Greek warrior helmet" appearance of the nose (wide bridge of the nose continuing to the forehead), microcephaly, high anterior hairline with prominent glabella, widely spaced eyes, epicanthus, highly arched eyebrows, short philtrum, downturned corners of the mouth, micrognathia, and poorly formed ears with pits/tags. All affected individuals have prenatal-onset growth deficiency followed by postnatal growth retardation and hypotonia with muscle underdevelopment. Developmental delay/intellectual disability of variable degree is present in all. Seizures occur in 90% to 100% of children with WHS. Other findings include skeletal anomalies (60%-70%), congenital heart defects (~50%), hearing loss (mostly conductive) (>40%), urinary tract malformations (25%), and structural brain abnormalities (33%).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 4:1980758
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
KCNJ11
Variant:
c.1094G>A
(p.Arg365His)
rsID: rs750689750
Ref Allele: C
Alt Allele: T
Freq: 0.0024%rare
CADD: 23.3
ClinVar Submissions (1)
Familial hyperinsulinism (referred to as FHI in this GeneReview) is characterized by hypoglycemia that ranges from severe neonatal-onset, difficult-to-manage disease to childhood-onset disease with mild symptoms and difficult-to-diagnose hypoglycemia. Neonatal-onset disease manifests within hours to two days after birth. Childhood-onset disease manifests during the first months or years of life. In the newborn period, presenting symptoms may be nonspecific, including seizures, hypotonia, poor feeding, and apnea. In severe cases, serum glucose concentrations are typically extremely low and thus easily recognized, whereas in milder cases, variable and mild hypoglycemia may make the diagnosis more difficult. Even within the same family, disease manifestations can range from mild to severe. Individuals with autosomal recessive familial hyperinsulinism, caused by pathogenic variants in either ABCC8 or KCNJ11 (FHI-KATP), tend to be large for gestational age and usually present with severe refractory hypoglycemia in the first 48 hours of life; affected infants usually respond only partially to diet or medical management (i.e., diazoxide therapy) and thus may require pancreatic resection. Individuals with autosomal dominant FHI-KATP tend to be appropriate for gestational age at birth, to present at approximately age one year (range: 2 days - 30 years), and to respond to diet and diazoxide therapy. Exceptions to both of these generalities have been reported. FHI-GCK, caused by pathogenic variants in GCK, may be much milder than FHI-KATP; however, some persons have severe, diazoxide-unresponsive hypoglycemia. FHI-HADH, caused by pathogenic variants in HADH, tends to be relatively mild, although severe cases have been reported. Individuals with FHI-HNF4A, caused by pathogenic variants in HNF4A, are typically born large for gestational age and have mild features that respond to diazoxide treatment. FHI-UCP2, caused by pathogenic variants in UCP2, is a rare cause of diazoxide-responsive FH1. Hyperammonemia/hyperinsulinism (HA/HI) is associated with mild-to-moderate hyperammonemia and with relatively mild, late-onset hypoglycemia; most but not all affected individuals have pathogenic variants in GLUD1.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 11:17386998
Permanent neonatal diabetes mellitus (PNDM) is characterized by the onset of hyperglycemia within the first six months of life (mean age: 7 weeks; range: birth to 26 weeks). The diabetes mellitus is associated with partial or complete insulin deficiency. Clinical manifestations at the time of diagnosis include intrauterine growth retardation, hyperglycemia, glycosuria, osmotic polyuria, severe dehydration, and failure to thrive. Therapy with insulin corrects the hyperglycemia and results in dramatic catch-up growth. The course of PNDM varies by genotype.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 11:17386998
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 11:17386998
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
KIF5C
Variant:
c.-44G>A
rsID: rs557953832
Ref Allele: G
Alt Allele: A
Freq: 0.0032%rare
CADD: 9.927
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 16, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:148875574
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
TTN
Variant:
c.75745C>T
(p.Arg25249Cys)
rsID: rs397517702
Ref Allele: G
Alt Allele: A
Freq: 0.0032%rare
CADD: 24.5
ClinVar Submissions (4)
Last Evaluated: Dec 18, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178570387
Limb-girdle muscular dystrophy is a term for a group of diseases that cause weakness and wasting of the muscles in the arms and legs. The muscles most affected are those closest to the body (proximal muscles), specifically the muscles of the shoulders, upper arms, pelvic area, and thighs.The severity, age of onset, and features of limb-girdle muscle dystrophy vary among the many subtypes of this condition and may be inconsistent even within the same family. Signs and symptoms may first appear at any age and generally worsen with time, although in some cases they remain mild.In the early stages of limb-girdle muscular dystrophy, affected individuals may have an unusual walking gait, such as waddling or walking on the balls of their feet, and may also have difficulty running. They may need to use their arms to press themselves up from a squatting position because of their weak thigh muscles. As the condition progresses, people with limb-girdle muscular dystrophy may eventually require wheelchair assistance.Muscle wasting may cause changes in posture or in the appearance of the shoulder, back, and arm. In particular, weak shoulder muscles tend to make the shoulder blades (scapulae) "stick out" from the back, a sign known as scapular winging. Affected individuals may also have an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Some develop joint stiffness (contractures) that can restrict movement in their hips, knees, ankles, or elbows. Overgrowth (hypertrophy) of the calf muscles occurs in some people with limb-girdle muscular dystrophy.Weakening of the heart muscle (cardiomyopathy) occurs in some forms of limb-girdle muscular dystrophy. Some affected individuals experience mild to severe breathing problems related to the weakness of muscles needed for breathing. In some cases, the breathing problems are severe enough that affected individuals need to use a machine to help them breathe (mechanical ventilation).Intelligence is generally unaffected in limb-girdle muscular dystrophy; however, developmental delay and intellectual disability have been reported in rare forms of the disorder.
Last Evaluated: Dec 18, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178570387
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 18, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178570387
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
EHMT1
Variant:
c.3687C>T
(p.Thr1229=)
rsID: rs201655114
Ref Allele: C
Alt Allele: T
Freq: 0.0032%rare
CADD: 18.31
ClinVar Submissions (2)
Kleefstra syndrome is characterized by intellectual disability, childhood hypotonia, and distinctive facial features. The majority of individuals function in the moderate to severe spectrum of intellectual disability although a few individuals have mild delay and total IQ around 70. Although most have severe expressive speech delay with little speech development, general language development is usually at a higher level, making nonverbal communication possible. A complex pattern of other findings can also be observed including heart defects, renal/urologic defects, genital defects in males, severe respiratory infections, epilepsy/febrile seizures, autistic-like features in childhood, and extreme apathy or catatonic-like features after puberty.
Last Evaluated: Jun 20, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:137834495
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 20, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:137834495
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
GATM
Variant:
c.885C>A
(p.Ser295=)
rsID: rs3210029
Ref Allele: G
Alt Allele: T
Freq: 0.0032%rare
CADD: 11.33
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 22, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 15:45366139
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
RYR2
Variant:
c.9085A>G
(p.Ile3029Val)
rsID: rs370141970
Ref Allele: A
Alt Allele: G
Freq: 0.004%rare
CADD: 18.61
ClinVar Submissions (3)
Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).
Last Evaluated: Dec 05, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:237698982
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by episodic syncope occurring during exercise or acute emotion in individuals without structural cardiac abnormalities. The underlying cause of these episodes is the onset of fast ventricular tachycardia (bidirectional or polymorphic). Spontaneous recovery may occur when these arrhythmias self-terminate. In other instances, ventricular tachycardia may degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation is not readily available. The mean age of onset of symptoms (usually a syncopal episode) is between age seven and twelve years; onset as late as the fourth decade of life has been reported. If untreated, CPVT is highly lethal, as approximately 30% of affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. Sudden death may be the first manifestation of the disease.
Last Evaluated: Dec 05, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:237698982
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 05, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:237698982
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
MARS
Variant:
c.1369-11C>T
rsID: rs377436527
Ref Allele: C
Alt Allele: T
Freq: 0.004%rare
CADD: 5.43
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 04, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 12:57511687
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
UNC13D
Variant:
c.3142G>A
(p.Ala1048Thr)
rsID: rs758781229
Ref Allele: C
Alt Allele: T
Freq: 0.004%rare
CADD: 14.47
ClinVar Submissions (1)
Familial hemophagocytic lymphohistiocytosis (FHL) is characterized by proliferation and infiltration of hyperactivated macrophages and T-lymphocytes manifesting as acute illness with prolonged fever, cytopenias, and hepatosplenomegaly. Onset is typically within the first months or years of life and, on occasion, in utero, although later childhood or adult onset is more common than previously suspected. Neurologic abnormalities may be present initially or may develop later; they may include increased intracranial pressure, irritability, neck stiffness, hypotonia, hypertonia, convulsions, cranial nerve palsies, ataxia, hemiplegia, quadriplegia, blindness, and coma. Rash and lymphadenopathy are less common. Other findings include liver dysfunction and bone marrow hemophagocytosis. The median survival of children with typical FHL, without treatment, is less than two months; progression of hemophagocytic lymphohistiocytosis and infection account for the majority of deaths in untreated individuals.
Last Evaluated: Jan 08, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 17:75828796
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
ACOX1
Variant:
c.867T>C
(p.Ala289=)
rsID: rs370001667
Ref Allele: A
Alt Allele: G
Freq: 0.004%rare
CADD: 6.932
ClinVar Submissions (1)
Peroxisomal acyl-CoA oxidase deficiency is a disorder of peroxisomal fatty acid beta-oxidation. See also D-bifunctional protein deficiency (261515), caused by mutation in the HSD17B4 gene (601860) on chromosome 5q2. The clinical manifestations of these 2 deficiencies are similar to those of disorders of peroxisomal assembly, including Zellweger cerebrohepatorenal syndrome (see 214100) and neonatal adrenoleukodystrophy (see 601539) (Watkins et al., 1995).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 17:75953528
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
MYOM1
Variant:
c.290G>T
(p.Gly97Val)
rsID: rs568600892
Ref Allele: C
Alt Allele: A
Freq: 0.004%rare
CADD: 23.1
ClinVar Submissions (2)
A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.
Last Evaluated: Mar 12, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 18:3214934
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 12, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 18:3214934
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
COL5A1
Variant:
c.12T>C
(p.His4=)
rsID: rs368818087
Ref Allele: T
Alt Allele: C
Freq: 0.0048%rare
CADD: 20.2
ClinVar Submissions (3)
Last Evaluated: May 24, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:134642199
Classic Ehlers-Danlos syndrome (cEDS) is a connective tissue disorder characterized by skin hyperextensibility, atrophic scarring, and generalized joint hypermobility (GJH). The skin is soft and doughy to the touch, and hyperextensible, extending easily and snapping back after release (unlike lax, redundant skin, as in cutis laxa). The skin is fragile, as manifested by splitting of the dermis following relatively minor trauma, especially over pressure points (knees, elbows) and areas prone to trauma (shins, forehead, chin). Wound healing is poor, and stretching of scars after apparently successful primary wound healing is characteristic. Complications of joint hypermobility, such as dislocations of the shoulder, patella, digits, hip, radius, and clavicle, usually resolve spontaneously or are easily managed by the affected individual. Other features include hypotonia with delayed motor development, fatigue and muscle cramps, and easy bruising. Mitral valve prolapse can occur infrequently, but tends to be of little clinical consequence. Aortic root dilatation has been reported, appears to be more common in young individuals, and rarely progresses.
Last Evaluated: May 24, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:134642199
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 24, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:134642199
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
TYK2
Variant:
c.1670-19A>G
rsID: rs534465521
Ref Allele: T
Alt Allele: C
Freq: 0.0048%rare
CADD: 5.073
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 19:10362200
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
SYP
Variant:
c.*969G>A
rsID: rs782481686
Ref Allele: C
Alt Allele: T
Freq: 0.0048%rare
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: X:49188318
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Homo
Gene:
P3H1
Variant:
c.1838+8C>T
rsID: rs549922561
Ref Allele: G
Alt Allele: A
Freq: 0.0056%rare
CADD: 1.775
ClinVar Submissions (1)
Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most forms of OI are autosomal dominant with mutations in one of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160). Cabral et al. (2007) described a form of autosomal recessive OI, which they designated OI type VIII, characterized by white sclerae, severe growth deficiency, extreme skeletal undermineralization, and bulbous metaphyses.
Last Evaluated: Dec 28, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:42748192
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
KCND3
Variant:
c.1348C>T
(p.Leu450Phe)
rsID: rs150401343
Ref Allele: G
Alt Allele: A
Freq: 0.0056%rare
CADD: 22.3
ClinVar Submissions (6)
Brugada syndrome is characterized by cardiac conduction abnormalities (ST-segment abnormalities in leads V1-V3 on ECG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and the sudden unexpected nocturnal death syndrome (SUNDS), a typical presentation in individuals from Southeast Asia. Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome.
Last Evaluated: Feb 01, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:111780713
OMIM Allelic Variant: 605411.0005
Last Evaluated: Feb 01, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:111780713
OMIM Allelic Variant: 605411.0005
The hereditary ataxias are a group of genetic disorders characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs. In this GeneReview the hereditary ataxias are categorized by mode of inheritance and gene (or chromosome locus) in which pathogenic variants occur.
Last Evaluated: Feb 01, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:111780713
OMIM Allelic Variant: 605411.0005
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 01, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:111780713
OMIM Allelic Variant: 605411.0005
This individual has one copy of the genetic mutation, and because the condition(s) are autosomal dominant, they may manifest the condition rather than just being a carrier. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
MEN1
Variant:
c.913-42G>C
rsID: rs529037188
Ref Allele: C
Alt Allele: G
Freq: 0.0056%rare
CADD: 9.17
ClinVar Submissions (1)
Multiple endocrine neoplasia type 1 (MEN1) syndrome includes varying combinations of more than 20 endocrine and non-endocrine tumors. Endocrine tumors become evident either by overproduction of hormones by the tumor or by growth of the tumor itself. Parathyroid tumors are the main MEN1-associated endocrinopathy; onset in 90% of individuals is between ages 20 and 25 years with hypercalcemia evident by age 50 years; hypercalcemia causes lethargy, depression, confusion, anorexia, constipation, nausea, vomiting, diuresis, dehydration, hypercalciuria, kidney stones, increased bone resorption/fracture risk, hypertension, and shortened QT interval. Pituitary tumors include prolactinoma (the most common), which manifests as oligomenorrhea/amenorrhea and galactorrhea in females and sexual dysfunction in males. Well-differentiated endocrine tumors of the gastro-entero-pancreatic (GEP) tract can manifest as Zollinger-Ellison syndrome (gastrinoma); hypoglycemia (insulinoma); hyperglycemia, anorexia, glossitis, anemia, diarrhea, venous thrombosis, and skin rash (glucagonoma); and watery diarrhea, hypokalemia, and achlorhydria syndrome (vasoactive intestinal peptide [VIP]-secreting tumor). Carcinoid tumors are non-hormone-secreting and can manifest as a large mass after age 50 years. Adrenocortical tumors can be associated with primary hypercortisolism or hyperaldosteronism. Non-endocrine tumors include facial angiofibromas, collagenomas, lipomas, meningiomas, ependymomas, and leiomyomas.
Last Evaluated: May 16, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:64806410
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
KCNJ1
Variant:
c.762C>T
(p.Asp254=)
rsID: rs142030262
Ref Allele: G
Alt Allele: A
Freq: 0.0056%rare
CADD: 11.07
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 05, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:128839539
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
TRPM1
Variant:
c.1219C>A
(p.Pro407Thr)
rsID: rs374376006
Ref Allele: G
Alt Allele: T
Freq: 0.0056%rare
CADD: 16.41
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 15:31050561
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
TTBK2
Variant:
c.1354G>A
(p.Glu452Lys)
rsID: rs527763642
Ref Allele: C
Alt Allele: T
Freq: 0.0056%rare
CADD: 26.1
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 30, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 15:42777086
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
OTOA
Variant:
c.1141C>G
(p.Gln381Glu)
rsID: rs377581131
Ref Allele: C
Alt Allele: G
Freq: 0.0056%rare
CADD: 22.7
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 23, 2015
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:21709924
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
NEB
Variant:
c.863A>G
(p.Lys288Arg)
rsID: rs202035863
Ref Allele: T
Alt Allele: C
Freq: 0.0064%rare
CADD: 26.3
ClinVar Submissions (4)
Last Evaluated: Dec 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:151710498
Nemaline myopathy (referred to in this entry as NM) is characterized by weakness, hypotonia, and depressed or absent deep tendon reflexes. Muscle weakness is usually most severe in the face, the neck flexors, and the proximal limb muscles. The clinical classification defines six forms of NM, which are classified by onset and severity of motor and respiratory involvement: Severe congenital (neonatal) (16% of all individuals with NM). Amish NM. Intermediate congenital (20%). Typical congenital (46%). Childhood-onset (13%). Adult-onset (late-onset) (4%). Considerable overlap occurs among the forms. There are significant differences in survival between individuals classified as having severe, intermediate, and typical congenital NM. Severe neonatal respiratory disease and the presence of arthrogryposis multiplex congenita are associated with death in the first year of life. Independent ambulation before age 18 months is predictive of survival. Most children with typical congenital NM are eventually able to walk.
Last Evaluated: Dec 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:151710498
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:151710498
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
AGPAT2
Variant:
c.199G>A
(p.Val67Met)
rsID: rs563539429
Ref Allele: C
Alt Allele: T
Freq: 0.0064%rare
CADD: 22.4
ClinVar Submissions (1)
Diabetes mellitus caused by mutation(s) in a single gene, usually presenting in childhood or early adulthood.
Last Evaluated: Jul 19, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:136677540
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
COL4A2
Variant:
c.1339+14A>G
rsID: rs368543918
Ref Allele: A
Alt Allele: G
Freq: 0.0064%rare
CADD: 4.735
ClinVar Submissions (1)
A cavity within the cerebral hemisphere, filled with cerebrospinal fluid, that communicates directly with the ventricular system. [HPO:probinson, PMID:9279052]
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 13:110450468
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
FLG
Variant:
c.7031C>G
(p.Ser2344Ter)
rsID: rs372754256
Ref Allele: G
Alt Allele: C
Freq: 0.0072%rare
CADD: 36
ClinVar Submissions (2)
Diseases that are caused by genetic mutations present during embryo or fetal development, although they may be observed later in life. The mutations may be inherited from a parent's genome or they may be acquired in utero.
Last Evaluated: Nov 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 1:152307855
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Nov 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 1:152307855
The data does not specify whether the genetic variant is autosomal recessive or autosomal dominant. For a definitive determination, refer to resources such as OMIM.
Clinically Significant Pathogenic
Hetero
Gene:
BRCA1
Variant:
c.4357+651A>G
rsID: rs530463308
Ref Allele: T
Alt Allele: C
Freq: 0.0072%rare
CADD: 9.611
ClinVar Submissions (1)
BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The exact cancer risks differ slightly depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant.
Last Evaluated: Sep 28, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:43081753
Expert Reviewed Benign
Hetero
Gene:
PRPF31
Variant:
c.*46G>A
rsID: rs368621219
Ref Allele: G
Alt Allele: A
Freq: 0.0072%rare
CADD: 1.314
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 19:54131478
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
NPHP4
Variant:
c.1490C>G
(p.Pro497Arg)
rsID: rs375051705
Ref Allele: G
Alt Allele: C
Freq: 0.008%rare
CADD: 25
ClinVar Submissions (2)
The nephronophthisis (NPH) phenotype is characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before age 30 years. Three age-based clinical subtypes are recongnized: infantile, juvenile, and adolescent/adult. Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia and facial dysmorphisms) or postnatally with renal manifestations that progress to ESRD before age 3 years. Juvenile NPH, the most prevalent subtype, typically presents with polydipsia and polyuria, growth retardation, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD). Hypertension is typically absent due to salt wasting. ESRD develops at a median age of 13 years. Ultrasound findings are increased echogenicity, reduced corticomedullary differentiation, and renal cysts (in 50% of affected individuals). Histologic findings include tubulointerstitial fibrosis, thickened and disrupted tubular basement membrane, sporadic corticomedullary cysts, and normal or reduced kidney size. Adolescent/ adult NPH is clinically similar to juvenile NPH, but ESRD develops at a median age of 19 years. Within a subtype inter- and intrafamilial variability in rate of progression to ESRD is considerable. Approximately 80%-90% of individuals with the NPH phenotype have no extrarenal features (i.e., they have isolated NPH); ~10%-20% have extrarenal manifestations that constitute a recognizable syndrome (e.g., Joubert syndrome, Bardet-Biedl syndrome, Jeune syndrome and related skeletal disorders, Meckel-Gruber syndrome, Senior-Løken syndrome, Leber congenital amaurosis, COACH syndrome, and oculomotor apraxia, Cogan type).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:5909165
Senior-Loken syndrome is an autosomal recessive disease with the main features of nephronophthisis (NPHP; see 256100) and Leber congenital amaurosis (see 204000). Mutations in some of the same genes that cause nephronophthisis (see 256100) cause Senior-Loken syndrome. Genetic Heterogeneity of Senior-Loken Syndrome Other forms of SLSN include SLSN4 (606996), caused by mutation in the NPHP4 gene (607215) on chromosome 1p36; SLSN5 (609254), caused by mutation in the NPHP5 gene (IQCB1; 609237) on chromosome 3q13; SLSN6 (610189), caused by mutation in the NPHP6 gene (CEP290; 610142) on chromosome 12q21; SLSN7 (613615), caused by mutation in the SDCCAG8 gene (613524) on chromosome 1q43; SLSN8 (616307), caused by mutation in the WDR19 gene (608151) on chromosome 4p14; and SLSN9 (616629), caused by mutation in the TRAF3IP1 gene (607380) on chromosome 2q37. Another form of SLSN, SLSN3 (606995), has been mapped to a locus on chromosome 3q22, overlapping the NPHP3 locus (604387).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:5909165
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
EGR2
Variant:
c.1352G>T
(p.Gly451Val)
rsID: rs138967272
Ref Allele: C
Alt Allele: A
Freq: 0.008%rare
CADD: 10.21
ClinVar Submissions (2)
Charcot-Marie-Tooth disease encompasses a group of disorders called hereditary sensory and motor neuropathies that damage the peripheral nerves. Peripheral nerves connect the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound. Damage to the peripheral nerves that worsens over time can result in alteration or loss of sensation and wasting (atrophy) of muscles in the feet, legs, and hands.Charcot-Marie-Tooth disease usually becomes apparent in adolescence or early adulthood, but onset may occur anytime from early childhood through late adulthood. Symptoms of Charcot-Marie-Tooth disease vary in severity and age of onset even among members of the same family. Some people never realize they have the disorder because their symptoms are so mild, but most have a moderate amount of physical disability. A small percentage of people experience severe weakness or other problems which, in very rare cases, can be life-threatening. In most affected individuals, however, Charcot-Marie-Tooth disease does not affect life expectancy.Typically, the earliest symptoms of Charcot-Marie-Tooth disease result from muscle atrophy in the feet. Affected individuals may have foot abnormalities such as high arches (pes cavus), flat feet (pes planus), or curled toes (hammer toes). They often have difficulty flexing the foot or walking on the heel of the foot. These difficulties may cause a higher than normal step (steppage gait) and increase the risk of ankle injuries and tripping. As the disease worsens, muscles in the lower legs usually weaken, but leg and foot problems rarely require the use of a wheelchair.Affected individuals may also develop weakness in the hands, causing difficulty with daily activities such as writing, fastening buttons, and turning doorknobs. People with Charcot-Marie-Tooth disease typically experience a decreased sensitivity to touch, heat, and cold in the feet and lower legs, but occasionally feel aching or burning sensations. In rare cases, affected individuals have loss of vision or gradual hearing loss that sometimes leads to deafness.There are several types of Charcot-Marie-Tooth disease, which are differentiated by their effects on nerve cells and patterns of inheritance. Type 1 (CMT1) is characterized by abnormalities in myelin, the fatty substance that covers nerve cells, protecting them and helping to transmit nerve impulses. These abnormalities slow the transmission of nerve impulses and can affect the health of the nerve fiber. Type 2 (CMT2) is characterized by abnormalities in the fiber, or axon, that extends from a nerve cell body to muscles or to sense organs. These abnormalities reduce the strength of the nerve impulse. In forms of Charcot-Marie-Tooth disease classified as intermediate type, the nerve impulses are both slowed and reduced in strength, probably due to abnormalities in both myelin and axons. Type 4 (CMT4) is distinguished from the other types by its pattern of inheritance; it can affect either the axons or the myelin. Type X Charcot-Marie-Tooth disease (CMTX) is caused by mutations in genes on the X chromosome, one of the two sex chromosomes. Within the various types of Charcot-Marie-Tooth disease, subtypes (such as CMT1A, CMT1B, CMT2A, CMT4A, and CMTX1) indicate different genetic causes.Sometimes other, historical names are used to refer to particular forms of Charcot-Marie-Tooth disease. For example, Roussy-Levy syndrome is a form of CMT11 with the additional feature of rhythmic shaking (tremors). Dejerine-Sottas syndrome is a term sometimes used to describe a severe, early childhood form of Charcot-Marie-Tooth disease; it is also sometimes called type 3 (CMT3). Depending on the specific gene that is altered, this severe, early-onset form of the disorder may also be classified as CMT1 or CMT4. CMTX5 is also known as Rosenberg-Chutorian syndrome.
Last Evaluated: Nov 24, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:62813286
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
BRCA1
Variant:
c.4186-2187C>T
rsID: rs562679568
Ref Allele: G
Alt Allele: A
Freq: 0.008%rare
CADD: 17.04
ClinVar Submissions (1)
BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The exact cancer risks differ slightly depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant.
Last Evaluated: Sep 28, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:43084762
Expert Reviewed Benign
Hetero
Gene:
BRCA2
Variant:
c.9257-5114T>C
rsID: rs11571802
Ref Allele: T
Alt Allele: C
Freq: 0.0088%rare
CADD: 9.744
ClinVar Submissions (1)
BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The exact cancer risks differ slightly depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant.
Last Evaluated: Sep 28, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:32389575
Expert Reviewed Benign
Hetero
Gene:
BRCA1
Variant:
c.80+1470A>T
rsID: rs541281969
Ref Allele: T
Alt Allele: A
Freq: 0.0088%rare
CADD: 4.13
ClinVar Submissions (1)
BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The exact cancer risks differ slightly depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant.
Last Evaluated: Sep 28, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:43122547
Expert Reviewed Benign
Hetero
Gene:
TMEM237
Variant:
c.*2465A>G
rsID: rs527921749
Ref Allele: T
Alt Allele: C
Freq: 0.0096%rare
CADD: 5.068
ClinVar Submissions (1)
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:201621790
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
SPTBN2
Variant:
c.2262C>T
(p.Ala754=)
rsID: rs368022952
Ref Allele: G
Alt Allele: A
Freq: 0.0096%rare
CADD: 0.358
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 25, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:66705014
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
PHEX
Variant:
c.118+7G>T
rsID: rs534550003
Ref Allele: G
Alt Allele: T
Freq: 0.0096%rare
ClinVar Submissions (1)
The phenotypic spectrum of X-linked hypophosphatemia (XLH) ranges from isolated hypophosphatemia to severe lower-extremity bowing. XLH frequently manifests in the first two years of life when lower-extremity bowing becomes evident with the onset of weight bearing; however, it sometimes is not manifest until adulthood, as previously unevaluated short stature. In adults, enthesopathy (calcification of the tendons, ligaments, and joint capsules) associated with joint pain and impaired mobility may be the initial presenting complaint. Persons with XLH are prone to spontaneous dental abscesses; sensorineural hearing loss has also been reported.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: X:22033130
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Homo
Gene:
SPAST
Variant:
c.*1995A>G
rsID: rs540679757
Ref Allele: A
Alt Allele: G
Freq: 0.0111%rare
CADD: 5.428
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:32156491
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
FOXI1
Variant:
c.308G>C
(p.Gly103Ala)
rsID: rs370450076
Ref Allele: G
Alt Allele: C
Freq: 0.0111%rare
CADD: 19.4
ClinVar Submissions (2)
Last Evaluated: Jan 24, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 5:170106265
Pendred syndrome/nonsyndromic enlarged vestibular aqueduct (PDS/NSEVA) comprises a phenotypic spectrum of sensorineural hearing loss (SNHL) that is usually congenital and often severe to profound (although mild-to-moderate progressive hearing impairment also occurs), vestibular dysfunction, and temporal bone abnormalities (bilateral enlarged vestibular aqueduct with or without cochlear hypoplasia). PDS also includes development of euthyroid goiter in late childhood to early adulthood whereas NSEVA does not.
Last Evaluated: Jan 24, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 5:170106265
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 24, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 5:170106265
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
IL17RA
Variant:
c.*2163G>C
rsID: rs543545127
Ref Allele: G
Alt Allele: C
Freq: 0.0111%rare
CADD: 2.403
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 22:17111983
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
IL17RA
Variant:
c.*3976G>A
rsID: rs576803215
Ref Allele: G
Alt Allele: A
Freq: 0.0111%rare
CADD: 0.689
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 22:17113796
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
BAP1
Variant:
c.*643G>A
rsID: rs374367093
Ref Allele: C
Alt Allele: T
Freq: 0.0119%rare
CADD: 0.247
ClinVar Submissions (1)
BAP1 tumor predisposition syndrome (BAP1-TPDS) is associated with an increased risk for the specific skin lesion – atypical Spitz tumors – and the following cancers, in descending order of frequency: uveal (eye) melanoma (UM), malignant mesothelioma (MMe), cutaneous melanoma (CM), clear cell renal cell carcinoma (ccRCC), and basal cell carcinoma (BCC). Affected individuals can have more than one type of primary cancer. In general the median age of onset of these tumors is younger than in the general population. UM tends to be a more aggressive class 2 tumor with higher risk for metastasis and reduced survival compared to UM that occurs in the general population. However, because of the limited number of families reported to date, the penetrance, natural history, and frequencies of the BAP1-associated tumors are yet to be determined. Other suspected but unconfirmed tumors in BAP1-TPDS include (in alphabetic order): breast cancer, cholangiocarcinoma, non-small cell lung adenocarcinoma (NSCLC), meningioma, and neuroendocrine carcinoma.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:52401645
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
MYO5B
Variant:
c.2228G>A
(p.Arg743His)
rsID: rs368212890
Ref Allele: C
Alt Allele: T
Freq: 0.0119%rare
CADD: 24.1
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 18:49906605
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
ZNF469
Variant:
c.10656C>T
(p.Asn3552=)
rsID: rs527707590
Ref Allele: C
Alt Allele: T
Freq: 0.0127%rare
CADD: 0.059
ClinVar Submissions (1)
Brittle cornea syndrome (BCS) is characterized by blue sclerae, corneal rupture after minor trauma, keratoconus or keratoglobus, hyperelasticity of the skin, and hypermobility of the joints (Al-Hussain et al., 2004). It is classified as a form of Ehlers-Danlos syndrome (Malfait et al., 2017). Genetic Heterogeneity of Brittle Cornea Syndrome Brittle cornea syndrome-2 (BCS2; 614170) is caused by mutation in the PRDM5 gene (614161) on chromosome 4q27.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 16:88438210
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
RUNX1
Variant:
c.*1823A>C
rsID: rs369678325
Ref Allele: T
Alt Allele: G
Freq: 0.0135%rare
CADD: 14.56
ClinVar Submissions (1)
Disease that is characterised by moderate thrombocytopenia, abnormal platelet function and the propensity to develop myeloid malignancies, in particular acute myelogenous leukaemia. The prevalence is unknown but the disease has been reported in less than 20 families. Causative mutations have been identified in the RUNX1 gene (also known as AML1 or CBFA2; chromosome 21q22.3) in most of the analysed families. The condition is inherited as an autosomal dominant trait.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 21:34790312
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
BSCL2
Variant:
c.-60G>A
rsID: rs3763853
Ref Allele: C
Alt Allele: T
Freq: 0.0159%rare
CADD: 24
ClinVar Submissions (2)
Last Evaluated: Nov 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:62705572
Last Evaluated: Nov 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:62705572
Last Evaluated: Nov 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:62705572
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
KRT74
Variant:
c.821T>C
(p.Phe274Ser)
rsID: rs147962513
Ref Allele: A
Alt Allele: G
Freq: 0.0159%rare
CADD: 33
ClinVar Submissions (3)
Some ectodermal dysplasias are here classified as congenital disorders characterized by abnormal development in 2 or more ectodermal structures (hair, nails, teeth, and sweat glands) without other systemic findings. Ectodermal dysplasia of the hair/nail type is a rare congenital condition characterized by hypotrichosis and nail dystrophy without nonectodermal or other ectodermal manifestations.
Last Evaluated: Dec 06, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:52571381
OMIM Allelic Variant: 608248.0004
Some ectodermal dysplasias are here classified as congenital disorders characterized by abnormal development in 2 or more ectodermal structures (hair, nails, teeth, and sweat glands) without other systemic findings. Ectodermal dysplasia of the hair/nail type is a rare congenital condition characterized by hypotrichosis and nail dystrophy without nonectodermal or other ectodermal manifestations.
Last Evaluated: Dec 06, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:52571381
OMIM Allelic Variant: 608248.0004
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 06, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:52571381
OMIM Allelic Variant: 608248.0004
This individual has one copy of the genetic mutation, and depending on the condition, this mutation can act as either autosomal dominant or recessive. Thus, they might manifest one condition while being a carrier for another. However, it's important to conduct thorough research before drawing definitive conclusions.
Clinically Significant Benign
Hetero
Gene:
CRX
Variant:
c.*2602C>T
rsID: rs562310108
Ref Allele: C
Alt Allele: T
Freq: 0.0159%rare
CADD: 1.584
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 19:47842569
Leber congenital amaurosis comprises a group of early-onset childhood retinal dystrophies characterized by vision loss, nystagmus, and severe retinal dysfunction. Patients usually present at birth with profound vision loss and pendular nystagmus. Electroretinogram (ERG) responses are usually nonrecordable. Other clinical findings may include high hypermetropia, photodysphoria, oculodigital sign, keratoconus, cataracts, and a variable appearance to the fundus (summary by Chung and Traboulsi, 2009). Genetic Heterogeneity of Leber Congenital Amaurosis LCA2 (204100) is caused by mutation in the RPE65 gene (RPE65; 180069) on chromosome 1p31. LCA3 (604232) is caused by mutation in the SPATA7 gene (609868) on chromosome 14q31. LCA4 (604393) is caused by mutation in the AIPL1 gene (604392) on chromosome 17p13. LCA5 (604537) is caused by mutation in the LCA5 gene (611408) on chromosome 6q14. LCA6 (613826) is caused by mutation in the RPGRIP1 gene (605446) on chromosome 14q11. LCA7 (613829) is caused by mutation in the CRX gene (602225) on chromosome 19q13. LCA8 (613835) is caused by mutation in the CRB1 gene (604210) on chromosome 1q31. LCA9 (608553) is caused by mutation in the NMNAT1 gene (608700) on chromosome 1p36. LCA10 (611755) is caused by mutation in the CEP290 gene (610142) on chromosome 12q21 and may account for as many as 21% of cases of LCA. LCA11 (613837) is caused by mutation in the IMPDH1 gene (146690) on chromosome 7q32. LCA12 (610612) is caused by mutation in the RD3 gene (180040) on chromosome 1q32. LCA13 (612712) is caused by mutation in the RDH12 gene (608830) on chromosome 14q24. LCA14 (613341) is caused by mutation in the LRAT gene (604863) on chromosome 4q32. LCA15 (613843) is caused by mutation in the TULP1 gene (602280) on chromosome 6p21. LCA16 (614186) is caused by mutation in the KCNJ13 gene (603208) on chromosome 2q37. LCA17 (615360) is caused by mutation in the GDF6 gene (601147) on chromosome 8q22. LCA18 (see 608133) is caused by mutation in the PRPH2 gene (179605) on chromosome 6p21. Perrault et al. (1999) provided a review of Leber congenital amaurosis, with emphasis on genetic heterogeneity. Wiszniewski et al. (2011) analyzed 13 known LCA genes in 60 LCA probands, and identified homozygous or compound heterozygous mutations in 42 (70%). In addition, a third disease-associated mutant allele at a second locus was identified in 7 (12%) of the 60 patients. Wiszniewski et al. (2011) stated that the significance of the third mutated allele was unknown, but suggested that mutational load might be important to penetrance of the LCA phenotype. Because LCA manifests very early in life and results in profound vision loss, patients with mutations in other syndromic or nonsyndromic eye disease genes may receive an initial diagnosis of LCA, prior to development of syndromic features or before more thorough phenotyping can be performed (see, e.g., Senior-Loken syndrome-5, 609254).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 19:47842569
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 19:47842569
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
VPS37A
Variant:
c.96G>C
(p.Leu32=)
rsID: rs199577037
Ref Allele: G
Alt Allele: C
Freq: 0.0167%rare
CADD: 15.93
ClinVar Submissions (1)
SPG53 is an autosomal recessive neurologic disorder characterized by onset in infancy of delayed motor development progressing to upper and lower limb spasticity with impaired walking. Affected individuals also show mild to moderate cognitive impairment (summary by Zivony-Elboum et al., 2012).
Last Evaluated: Nov 03, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 8:17247340
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
HYLS1
Variant:
c.24A>G
(p.Gly8=)
rsID: rs145001537
Ref Allele: A
Alt Allele: G
Freq: 0.0167%rare
CADD: 8.7
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 23, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:125899392
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
BRCA2
Variant:
c.8632+1347C>T
rsID: rs372507971
Ref Allele: C
Alt Allele: T
Freq: 0.0167%rare
CADD: 1.75
ClinVar Submissions (1)
BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The exact cancer risks differ slightly depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant.
Last Evaluated: Sep 28, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:32372447
Expert Reviewed Benign
Hetero
Gene:
AGPAT2
Variant:
c.189C>T
(p.Ile63=)
rsID: rs150180733
Ref Allele: G
Alt Allele: A
Freq: 0.0175%rare
CADD: 21.3
ClinVar Submissions (1)
Berardinelli-Seip congenital lipodystrophy (BSCL) is usually diagnosed at birth or soon thereafter. Because of the absence of functional adipocytes, lipid is stored in other tissues, including muscle and liver. Affected individuals develop insulin resistance and approximately 25%-35% develop diabetes mellitus between ages 15 and 20 years. Hepatomegaly secondary to hepatic steatosis and skeletal muscle hypertrophy occur in all affected individuals. Hypertrophic cardiomyopathy is reported in 20%-25% of affected individuals and is a significant cause of morbidity from cardiac failure and early mortality.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:136677550
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
CEACAM16
Variant:
c.51T>C
(p.Asn17=)
rsID: rs202230938
Ref Allele: T
Alt Allele: C
Freq: 0.0183%rare
CADD: 4.869
ClinVar Submissions (3)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 29, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:44703362
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
CPS1
Variant:
c.4404+4T>A
rsID: rs199739254
Ref Allele: T
Alt Allele: A
Freq: 0.0191%rare
CADD: 4.368
ClinVar Submissions (2)
Carbamoyl phosphate synthetase I deficiency is an autosomal recessive inborn error of metabolism of the urea cycle which causes hyperammonemia. There are 2 main forms: a lethal neonatal type and a less severe, delayed-onset type (summary by Klaus et al., 2009). Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis. Five disorders involving different defects in the biosynthesis of the enzymes of the urea cycle have been described: ornithine transcarbamylase deficiency (311250), carbamyl phosphate synthetase deficiency, argininosuccinate synthetase deficiency, or citrullinemia (215700), argininosuccinate lyase deficiency (207900), and arginase deficiency (207800).
Last Evaluated: Apr 04, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:210677140
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 04, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:210677140
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
DCLRE1C
Variant:
c.1368C>T
(p.Asn456=)
rsID: rs144654282
Ref Allele: G
Alt Allele: A
Freq: 0.0191%rare
CADD: 18.13
ClinVar Submissions (2)
Omenn syndrome is an inherited disorder of the immune system (immunodeficiency). Omenn syndrome is one of several forms of severe combined immunodeficiency (SCID), a group of disorders that cause individuals to have virtually no immune protection from bacteria, viruses, and fungi. Individuals with SCID are prone to repeated and persistent infections that can be very serious or life-threatening. Infants with Omenn syndrome typically experience pneumonia and chronic diarrhea. Often the organisms that cause infection in people with this disorder are described as opportunistic because they ordinarily do not cause illness in healthy people.In addition to immunodeficiency, children with Omenn syndrome develop autoimmunity, in which the immune system attacks the body's own tissues and organs. This abnormal immune reaction can cause very red skin (erythroderma), hair loss (alopecia), and an enlarged liver and spleen (hepatosplenomegaly). In addition, affected individuals have enlargement of tissues that produce infection-fighting white blood cells called lymphocytes. These include the thymus, which is a gland located behind the breastbone, and lymph nodes, which are found throughout the body.If not treated in a way that restores immune function, children with Omenn syndrome usually survive only until age 1 or 2.
Last Evaluated: Jul 24, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 10:14909119
Last Evaluated: Jul 24, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 10:14909119
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
SLC6A8
Variant:
c.1678A>G
(p.Met560Val)
rsID: rs145438966
Ref Allele: A
Alt Allele: G
Freq: 0.0191%rare
ClinVar Submissions (3)
The cerebral creatine deficiency syndromes (CCDS), inborn errors of creatine metabolism, include the two creatine biosynthesis disorders, guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency, and the creatine transporter (CRTR) deficiency. Intellectual disability and seizures are common to all three CCDS. The majority of individuals with GAMT deficiency have a behavior disorder that can include autistic behaviors and self-mutilation; about 40% have movement disorder. Onset is between ages three months and three years. Only 14 individuals with AGAT deficiency have been reported. The phenotype of CRTR deficiency in affected males ranges from mild intellectual disability and speech delay to severe intellectual disability, seizures, movement disorder and behavior disorder; age at diagnosis ranges from two to 66 years. Clinical phenotype of females heterozygous for CRTR deficiency ranges from asymptomatic to severe phenotype resembling male phenotype.
Last Evaluated: Dec 29, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: X:153694800
Last Evaluated: Dec 29, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: X:153694800
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 29, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: X:153694800
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Homo
Gene:
NPHP4
Variant:
c.944C>T
(p.Thr315Met)
rsID: rs200684272
Ref Allele: G
Alt Allele: A
Freq: 0.0199%rare
CADD: 24.4
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 20, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:5948118
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
APC
Variant:
c.136-1527G>A
rsID: rs76596358
Ref Allele: G
Alt Allele: A
Freq: 0.0199%rare
CADD: 0.593
ClinVar Submissions (1)
Colorectal cancer is a heterogeneous disease that is common in both men and women. In addition to lifestyle and environmental risk factors, gene defects can contribute to an inherited predisposition to CRC. CRC is caused by changes in different molecular pathogenic pathways, such as chromosomal instability, CpG island methylator phenotype, and microsatellite instability. Chromosome instability is the most common alteration and is present in almost 85% of all cases (review by Schweiger et al., 2013). Genetic Heterogeneity of Colorectal Cancer Mutations in a single gene result in a marked predisposition to colorectal cancer in 2 distinct syndromes: familial adenomatous polyposis (FAP; 175100) and hereditary nonpolyposis colorectal cancer (HNPCC; see 120435). FAP is caused by mutations in the APC gene (611731), whereas HNPCC is caused by mutations in several genes, including MSH2 (609309), MLH1 (120436), PMS1 (600258), PMS2 (600259), MSH6 (600678), TGFBR2 (190182), and MLH3 (604395). Epigenetic silencing of MSH2 results in a form of HNPCC (see HNPCC8, 613244). Other colorectal cancer syndromes include autosomal recessive adenomatous polyposis (608456), which is caused by mutations in the MUTYH gene (604933), and oligodontia-colorectal cancer syndrome (608615), which is caused by mutations in the AXIN2 gene (604025). The CHEK2 gene (604373) has been implicated in susceptibility to colorectal cancer in Finnish patients. A germline mutation in the PLA2G2A gene (172411) was identified in a patient with colorectal cancer. Germline susceptibility loci for colorectal cancer have also been identified. CRCS1 (608812) is conferred by mutation in the GALNT12 gene (610290) on chromosome 9q22; CRCS2 (611469) maps to chromosome 8q24; CRCS3 (612229) is conferred by variation in the SMAD7 gene (602932) on chromosome 18; CRCS4 (601228) is conferred by variation on 15q that causes increased and ectopic expression of the GREM1 gene (603054); CRCS5 (612230) maps to chromosome 10p14; CRCS6 (612231) maps to chromosome 8q23; CRCS7 (612232) maps to chromosome 11q23; CRCS8 (612589) maps to chromosome 14q22; CRCS9 (612590) maps to 16q22; CRCS10 (612591) is conferred by mutation in the POLD1 gene (174761) on chromosome 19q13; CRCS11 (612592) maps to chromosome 20p12; and CRCS12 (615083) is conferred by mutation in the POLE gene (174762) on chromosome 12q24. Somatic mutations in many different genes, including KRAS (190070), PIK3CA (171834), BRAF (164757), CTNNB1 (116806), FGFR3 (134934), AXIN2 (604025), AKT1 (164730), MCC (159350), MYH11 (160745), PARK2 (602544), and RNF43 (612482), have been identified in colorectal cancer.
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: other
Assembly: GRCh38
Chromosome/Position: 5:112764799
Hetero
Gene:
ATP6V0A4
Variant:
c.-137C>T
rsID: rs368646400
Ref Allele: G
Alt Allele: A
Freq: 0.0199%rare
CADD: 2.5
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:138798050
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
KRT5
Variant:
c.110G>A
(p.Arg37Gln)
rsID: rs61747181
Ref Allele: C
Alt Allele: T
Freq: 0.0231%rare
CADD: 20.9
ClinVar Submissions (1)
Epidermolysis bullosa simplex (EBS) is characterized by fragility of the skin (and mucosal epithelia in some cases) that results in non-scarring blisters and erosions caused by minor mechanical trauma. The current classification of epidermolysis bullosa (EB) includes two major types and 17 minor subtypes of EBS; all share the common feature of blistering above the dermal-epidermal junction at the ultrastructural level. The four most common subtypes of EBS are the focus of this GeneReview: EBS, localized (EBS-loc; previously known as Weber-Cockayne type). EBS, generalized intermediate (EBS-gen intermed; previously known as Koebner type). EBS-with mottled pigmentation (EBS-MP). EBS, generalized severe (EBS-gen sev; previously known as Dowling-Meara type). The phenotypes for these subtypes range from relatively mild blistering of the hands and feet to more generalized blistering, which can be fatal. In EBS-loc, blisters are rarely present or minimal at birth and may occur on the knees and shins with crawling or on the feet at approximately age 18 months; some individuals manifest the disease in adolescence or early adulthood. Blisters are usually confined to the hands and feet, but can occur anywhere if trauma is significant. In EBS, gen intermed, blisters may be present at birth or develop within the first few months of life. Involvement is more widespread than in EBS-loc, but generally milder than in EBS-gen sev. In EBS-MP, skin fragility is evident at birth and clinically indistinguishable from EBS-gen sev; over time, progressive brown pigmentation interspersed with hypopigmented spots develops on the trunk and extremities, with the pigmentation disappearing in adult life. Focal palmar and plantar hyperkeratoses may occur. In EBS-gen sev, onset is usually at birth; severity varies greatly, both among and within families. Widespread and severe blistering and/or multiple grouped clumps of small blisters are typical and hemorrhagic blisters are common. Improvement occurs during mid- to late childhood. Progressive hyperkeratosis of the palms and soles begins in childhood and may be the major complaint of affected individuals in adult life. Nail dystrophy and milia are common. Both hyper- and hypopigmentation can occur. Mucosal involvement in EBS-gen sev may interfere with feeding, especially in neonates and infants. Blistering can be severe enough to result in neonatal or infant death.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 12:52520187
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
FIGLA
Variant:
c.234A>T
(p.Ile78=)
rsID: rs199650129
Ref Allele: T
Alt Allele: A
Freq: 0.0239%rare
CADD: 14.08
ClinVar Submissions (1)
Premature ovarian failure is clearly a heterogeneous disorder. The terms 'hypergonadotropic ovarian failure' and 'hypergonadotropic ovarian dysgenesis' (see ODG1, 233300) have been used to indicate a group of disorders in which amenorrhea associated with elevated levels of serum gonadotropins occurs long before the age of 40 years (Coulam, 1982). Cytogenetic studies of X-chromosome aberrations have suggested that it is mainly the long arm of the X chromosome that is involved in defects of ovulation (Bione et al., 1998). Reviews Rossetti et al. (2017) reviewed the genetics of primary ovarian insufficiency, noting that the significance of this disorder was increasing because of the increasing number of women desiring conception beyond 30 years of age, at which point POF prevalence is more than 1%. Genetic Heterogeneity of Premature Ovarian Failure Mutations in genes identified within a region defined as POF2 (Xq13.3-q21.1) have been found to cause other forms of POF: POF2A (300511) by mutation in the DIAPH2 gene (300108) and POF2B (300604) by mutation in the POF1B gene (300603). See also POF3 (608996), caused by mutation in the FOXL2 gene (605597) on chromosome 3q22; POF4 (see 300510), caused by mutation in the BMP15 gene (300247) on chromosome Xp11; POF5 (611548), caused by mutation in the NOBOX gene (610934) on chromosome 7q35; POF6 (612310), caused by mutation in the FIGLA gene (608697) on chromosome 2p13; POF7 (612964), caused by mutation in the NR5A1 gene (184757) on chromosome 9q33; POF8 (615723), caused by mutation in the STAG3 gene (608489) on chromosome 7q22; POF9 (615724), caused by mutation in the HFM1 gene (615684) on chromosome 1p22; POF10 (612885), caused by mutation in the MCM8 gene (608187) on chromosome 20p12; POF11 (616946), caused by mutation in the ERCC6 gene (609413) on chromosome 10q11; POF12 (616947), caused by mutation in the SYCE1 gene (611486) on chromosome 10q26; POF13 (617442), caused by mutation in the MSH5 gene (603382) on chromosome 6p21; and POF14 (618014), caused by mutation in the GDF9 gene (601918) on chromosome 5q31. In 100 patients with primary or secondary amenorrhea before the age of 40 years, who also exhibited elevated FSH, Bouilly et al. (2016) screened for variants in 19 POF-associated or candidate genes. The authors noted that 8 of the 19 mutation-positive patients carried a genetic defect in more than 1 gene, and that patients with 2 or more variants tended to have a younger age of onset and were more likely have primary rather than secondary amenorrhea. Bouilly et al. (2016) suggested that digenicity and possibly oligogenicity may contribute to POF, noting that this might account for the phenotypic variability and incomplete penetrance that have been observed in patients with POF.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:70787799
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
NIPA1
Variant:
c.*1395C>T
rsID: rs537516417
Ref Allele: C
Alt Allele: T
Freq: 0.0239%rare
CADD: 0.403
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 15:22825634
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
G6PC
Variant:
c.*1304G>A
rsID: rs549833149
Ref Allele: G
Alt Allele: A
Freq: 0.0239%rare
CADD: 1.208
ClinVar Submissions (1)
Glycogen storage disease type I (GSDI) is characterized by accumulation of glycogen and fat in the liver and kidneys, resulting in hepatomegaly and renomegaly. The two subtypes (GSDIa and GSDIb) are clinically indistinguishable. Some untreated neonates present with severe hypoglycemia; more commonly, however, untreated infants present at age three to four months with hepatomegaly, lactic acidosis, hyperuricemia, hyperlipidemia, hypertriglyceridemia, and/or hypoglycemic seizures. Affected children typically have doll-like faces with fat cheeks, relatively thin extremities, short stature, and protuberant abdomen. Xanthoma and diarrhea may be present. Impaired platelet function can lead to a bleeding tendency with frequent epistaxis. Untreated GSDIb is associated with impaired neutrophil and monocyte function as well as chronic neutropenia after the first few years of life, all of which result in recurrent bacterial infections and oral and intestinal mucosal ulcers. Long-term complications of untreated GSDI include growth retardation resulting in short stature, osteoporosis, delayed puberty, gout, renal disease, pulmonary hypertension, hepatic adenomas with potential for malignant transformation, polycystic ovaries, pancreatitis, and changes in brain function. Normal growth and puberty is expected in treated children. Most affected individuals live into adulthood.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:42912730
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
PROC
Variant:
c.1161T>C
(p.Cys387=)
rsID: rs148855579
Ref Allele: T
Alt Allele: C
Freq: 0.0247%rare
CADD: 8.892
ClinVar Submissions (2)
Heterozygous protein C deficiency is characterized by recurrent venous thrombosis. However, many adults with heterozygous disease may be asymptomatic (Millar et al., 2000). Individuals with decreased amounts of protein C are classically referred to as having type I deficiency and those with normal amounts of a functionally defective protein as having type II deficiency (Bertina et al., 1984). Acquired protein C deficiency is a clinically similar disorder caused by development of an antibody against protein C. Clouse and Comp (1986) reviewed the structural and functional properties of protein C and discussed both hereditary and acquired deficiency of protein C.
Last Evaluated: Nov 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:127428721
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
DSC2
Variant:
c.348A>G
(p.Gln116=)
rsID: rs137941742
Ref Allele: T
Alt Allele: C
Freq: 0.0255%rare
CADD: 7.795
ClinVar Submissions (3)
Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).
Last Evaluated: Jan 04, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 18:31092107
Last Evaluated: Jan 04, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 18:31092107
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 04, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 18:31092107
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
ATL3
Variant:
c.1599A>G
(p.Arg533=)
rsID: rs201636843
Ref Allele: T
Alt Allele: C
Freq: 0.0279%rare
CADD: 4.661
ClinVar Submissions (1)
Hereditary sensory neuropathy type IF is an autosomal dominant sensory neuropathy affecting the lower limbs. Distal sensory impairment becomes apparent during the second or third decade of life, resulting in painless ulceration of the feet with poor healing, which can progress to osteomyelitis, bone destruction, and amputation. There is no autonomic involvement, spasticity, or cognitive impairment (summary by Kornak et al., 2014). For a discussion of genetic heterogeneity of HSN, see HSAN1A (162400).
Last Evaluated: Dec 05, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:63629346
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
KRT9
Variant:
c.222C>T
(p.Gly74=)
rsID: rs114665757
Ref Allele: G
Alt Allele: A
Freq: 0.0287%rare
CADD: 0.126
ClinVar Submissions (1)
Palmoplantar keratoderma (PPK) is a common hereditary cutaneous disorder characterized by marked hyperkeratosis on the surface of palms and soles (Hennies et al., 1995). PPK has been classified into diffuse, focal, and punctate forms according to the pattern of hyperkeratosis on the palms and soles (Lucker et al., 1994). Diffuse PPK develops at birth or shortly thereafter and involves the entire palm and sole with a sharp cutoff at an erythematous border; there are no lesions outside the volar skin, and, in particular, no follicular or oral lesions. In contrast, focal PPK is a late-onset form in which focal hyperkeratotic lesions develop in response to mechanical trauma; an important distinguishing feature is the presence of lesions at other body sites, e.g., oral and follicular hyperkeratosis (Stevens et al., 1996). Palmoplantar keratodermas can be further subdivided histologically into epidermolytic and nonepidermolytic PPK (Risk et al., 1994). Genetic Heterogeneity of Palmoplantar Keratoderma Nonepidermolytic palmoplantar keratoderma (NEPPK; 600962) is caused by mutation in the KRT1 gene. A focal form of NEPPK (FNEPPK1; 613000) is caused by mutation in the KRT16 gene (148067). Another focal form, FNEPPK2 (616400), is caused by mutation in the TRPV3 gene (607066); mutation in TRPV3 can also cause Olmsted syndrome (OLMS; 614594), a severe mutilating form of PPK. The diffuse Bothnian form of NEPPK (PPKB; 600231) is caused by mutation in the AQP5 gene (600442). The Nagashima type of nonepidermolytic diffuse PPK (PPKN; 615598) is caused by mutation in the SERPINB7 gene (603357). A generalized form of epidermolytic hyperkeratosis (EHK; 113800), also designated bullous congenital ichthyosiform erythroderma (BCIE), is caused by mutation in the keratin genes KRT1 and KRT10 (148080). For a discussion of punctate PPK, see 148600; for a discussion of striate PPK, see 148700.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 17:41571771
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
RAD51C
Variant:
c.*25C>G
rsID: rs28363336
Ref Allele: C
Alt Allele: G
Freq: 0.0295%rare
CADD: 1.352
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:58734247
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract – are more common in individuals with FA.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:58734247
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
IL7R
Variant:
c.153G>A
(p.Ser51=)
rsID: rs149235072
Ref Allele: G
Alt Allele: A
Freq: 0.0327%rare
CADD: 3.35
ClinVar Submissions (2)
Last Evaluated: Dec 19, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:35860922
Last Evaluated: Dec 19, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:35860922
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
FTCD
Variant:
c.368-15C>T
rsID: rs368792878
Ref Allele: G
Alt Allele: A
Freq: 0.0327%rare
CADD: 0.01
ClinVar Submissions (1)
Glutamate formiminotransferase deficiency is an autosomal recessive disorder and the second most common inborn error of folate metabolism. Features of a severe phenotype include elevated levels of formiminoglutamate (FIGLU) in the urine in response to histidine administration, megaloblastic anemia, and mental retardation. Features of a mild phenotype include high urinary excretion of FIGLU in the absence of histidine administration, mild developmental delay, and no hematologic abnormalities (summary by Hilton et al., 2003).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 21:46151995
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
SMARCAL1
Variant:
c.2226G>A
(p.Thr742=)
rsID: rs2271335
Ref Allele: G
Alt Allele: A
Freq: 0.0334%rare
CADD: 0.005
ClinVar Submissions (2)
Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive multisystem disorder characterized by spondyloepiphyseal dysplasia (SED) resulting in short stature, nephropathy, and T-cell deficiency. Radiographic manifestations of SED include ovoid and mildly flattened vertebral bodies, small deformed capital femoral epiphyses, and shallow dysplastic acetabular fossae. Adult height is 136-157 cm for men and 98.5-143 cm for women. Nearly all affected individuals have progressive steroid-resistant nephropathy, usually developing within five years of the diagnosis of growth failure and terminating with end-stage renal disease (ESRD). The majority of tested individuals have T-cell deficiency and an associated risk for opportunistic infection, a common cause of death. SIOD involves a spectrum that ranges from an infantile or severe early-onset form with death early in life to a juvenile or milder later-onset form with survival into adulthood if renal disease is appropriately treated.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:216468028
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:216468028
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
PRDM5
Variant:
c.1633T>C
(p.Tyr545His)
rsID: rs142515463
Ref Allele: A
Alt Allele: G
Freq: 0.0342%rare
CADD: 29.7
ClinVar Submissions (2)
Brittle cornea syndrome (BCS) is characterized by blue sclerae, corneal rupture after minor trauma, keratoconus or keratoglobus, hyperelasticity of the skin, and hypermobility of the joints (Al-Hussain et al., 2004). It is classified as a form of Ehlers-Danlos syndrome (Malfait et al., 2017). Genetic Heterogeneity of Brittle Cornea Syndrome Brittle cornea syndrome-2 (BCS2; 614170) is caused by mutation in the PRDM5 gene (614161) on chromosome 4q27.
Last Evaluated: Oct 31, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 4:120710404
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Oct 31, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 4:120710404
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
RELN
Variant:
c.7114G>A
(p.Val2372Met)
rsID: rs114344654
Ref Allele: C
Alt Allele: T
Freq: 0.0374%rare
CADD: 23.6
ClinVar Submissions (5)
Autosomal dominant epilepsy with auditory features (ADEAF) is a focal epilepsy syndrome with auditory symptoms and/or receptive aphasia as prominent ictal manifestations. The most common auditory symptoms are simple unformed sounds including humming, buzzing, or ringing; less common forms are distortions (e.g., volume changes) or complex sounds (e.g., specific songs or voices). Ictal receptive aphasia consists of a sudden onset of inability to understand language in the absence of general confusion. Less commonly, other ictal symptoms may occur, including sensory symptoms (visual, olfactory, vertiginous, or cephalic) or motor, psychic, and autonomic symptoms. Most affected individuals have focal to bilateral tonic-clonic seizures, usually accompanied by "focal aware" and "focal impaired-awareness" seizures, with auditory symptoms as a major focal aware seizure manifestation. Some persons have seizures precipitated by sounds such as a ringing telephone. Age at onset is usually in adolescence or early adulthood (range: age 4-50 years). The clinical course of ADEAF is benign. Seizures are usually well controlled after initiation of medical therapy.
Last Evaluated: May 21, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:103539144
Lissencephaly with cerebellar hypoplasia (LCH) affects brain development, resulting in the brain having a smooth appearance (lissencephaly) instead of its normal folds and grooves. In addition, the part of the brain that coordinates movement is unusually small and underdeveloped (cerebellar hypoplasia). Other parts of the brain are also often underdeveloped in LCH, including the hippocampus, which plays a role in learning and memory, and the part of the brain that is connected to the spinal cord (the brainstem).Individuals with LCH have moderate to severe intellectual disability and delayed development. They have few or no communication skills, extremely poor muscle tone (hypotonia), problems with coordination and balance (ataxia), and difficulty sitting or standing without support. Most affected children experience recurrent seizures (epilepsy) that begin within the first months of life. Some affected individuals have nearsightedness (myopia), involuntary eye movements (nystagmus), or puffiness or swelling caused by a buildup of fluids in the body's tissues (lymphedema).
Last Evaluated: May 21, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:103539144
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 21, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:103539144
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 21, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:103539144
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
SYNJ1
Variant:
c.822+7A>G
rsID: rs187016397
Ref Allele: T
Alt Allele: C
Freq: 0.0406%rare
CADD: 9.346
ClinVar Submissions (2)
Early infantile epileptic encephalopathy-53 is a severe neurodegenerative disorder characterized by onset of intractable seizures in infancy. Affected individuals show hypotonia and very poor or absent global development, resulting in severe intellectual disability and spastic quadriplegia. Some patients may die in childhood (summary by Hardies et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).
Last Evaluated: Mar 08, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 21:32695050
Parkinson disease-20 is an autosomal recessive neurodegenerative disorder characterized by young adult-onset of parkinsonism. Additional features may include seizures, cognitive decline, abnormal eye movements, and dystonia (summary by Krebs et al., 2013 and Quadri et al., 2013). For a phenotypic description and a discussion of genetic heterogeneity of Parkinson disease, see PD (168600).
Last Evaluated: Mar 08, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 21:32695050
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Mar 08, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 21:32695050
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
HSD17B4
Variant:
c.1767+8T>C
rsID: rs190659146
Ref Allele: T
Alt Allele: C
Freq: 0.0414%rare
CADD: 1.574
ClinVar Submissions (5)
D-bifunctional protein deficiency is a disorder of peroxisomal fatty acid beta-oxidation. See also peroxisomal acyl-CoA oxidase deficiency (264470), caused by mutation in the ACOX1 gene (609751) on chromosome 17q25. The clinical manifestations of these 2 deficiencies are similar to those of disorders of peroxisomal assembly, including X-linked adrenoleukodystrophy (ALD; 300100), Zellweger cerebrohepatorenal syndrome (see 214100) and neonatal adrenoleukodystrophy (NALD; see 601539) (Watkins et al., 1995). DBP deficiency has been classified into 3 subtypes depending upon the deficient enzyme activity. Type I is a deficiency of both 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase; type II is a deficiency of hydratase activity alone; and type III is a deficiency of dehydrogenase activity alone. Virtually all patients with types I, II, and III have a severe phenotype characterized by infantile-onset of hypotonia, seizures, and abnormal facial features, and most die before age 2 years. McMillan et al. (2012) proposed a type IV deficiency on the basis of less severe features; these patients have a phenotype reminiscent of Perrault syndrome (PRLTS1; 233400). Pierce et al. (2010) noted that Perrault syndrome and DBP deficiency overlap clinically and suggested that DBP deficiency may be underdiagnosed.
Last Evaluated: Dec 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:119527227
Perrault syndrome is a rare condition that causes different patterns of signs and symptoms in affected males and females. A key feature of this condition is hearing loss, which occurs in both males and females. Affected females also have abnormalities of the ovaries. Neurological problems occur in some affected males and females.In Perrault syndrome, the problems with hearing are caused by changes in the inner ear, which is known as sensorineural hearing loss. The impairment usually affects both ears and can be present at birth or begin in early childhood. Unless hearing is completely impaired at birth, the hearing problems worsen over time.Females with Perrault syndrome have abnormal or missing ovaries (ovarian dysgenesis), although their external genitalia are normal. Severely affected girls do not begin menstruation by age 16 (primary amenorrhea), and most never have a menstrual period. Less severely affected women have an early loss of ovarian function (primary ovarian insufficiency); their menstrual periods begin in adolescence, but they become less frequent and eventually stop before age 40. Women with Perrault syndrome may have difficulty conceiving or be unable to have biological children (infertile).Neurological problems in individuals with Perrault syndrome can include intellectual disability, difficulty with balance and coordinating movements (ataxia), and loss of sensation and weakness in the limbs (peripheral neuropathy). However, not everyone with this condition has neurological problems.
Last Evaluated: Dec 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:119527227
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:119527227
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:119527227
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
HSD17B4
Variant:
c.1512+25A>C
rsID: rs181609312
Ref Allele: A
Alt Allele: C
Freq: 0.0454%rare
CADD: 2.029
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 26, 2017
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:119509269
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
BMPR1A
Variant:
c.430+25G>A
rsID: rs200416589
Ref Allele: G
Alt Allele: A
Freq: 0.0454%rare
CADD: 3.567
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 10:86899915
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
CNGB1
Variant:
c.412+8C>A
rsID: rs185727761
Ref Allele: G
Alt Allele: T
Freq: 0.0462%rare
CADD: 8.539
ClinVar Submissions (3)
Last Evaluated: Nov 17, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 16:57962834
Last Evaluated: Nov 17, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 16:57962834
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 17, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 16:57962834
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
SLC45A2
Variant:
c.1352G>A
(p.Arg451His)
rsID: rs142680641
Ref Allele: C
Alt Allele: T
Freq: 0.051%rare
CADD: 11.89
ClinVar Submissions (3)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 20, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 5:33947179
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 20, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 5:33947179
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
PDE6A
Variant:
c.1614A>G
(p.Pro538=)
rsID: rs139697733
Ref Allele: T
Alt Allele: C
Freq: 0.0518%rare
CADD: 2.388
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 5:149896362
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
GLI3
Variant:
c.*2357T>A
rsID: rs562705224
Ref Allele: A
Alt Allele: T
Freq: 0.0534%rare
CADD: 1.272
ClinVar Submissions (1)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41961973
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41961973
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41961973
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
COL11A2
Variant:
c.4884G>C
(p.Glu1628Asp)
rsID: rs2229790
Ref Allele: C
Alt Allele: G
Freq: 0.0565%rare
CADD: 4.343
ClinVar Submissions (5)
Fibrochondrogenesis is a severe, autosomal recessive, short-limbed skeletal dysplasia clinically characterized by a flat midface with a small nose and anteverted nares, significant shortening of all limb segments but relatively normal hands and feet, and a small bell-shaped thorax with a protuberant abdomen. Radiographically, the long bones are short and have broad metaphyseal ends, giving them a dumb-bell shape. The vertebral bodies are flat and, on lateral view, have a distinctive pinched appearance, with a hypoplastic posterior end and a rounded anterior end. The ribs are typically short and wide and have metaphyseal cupping at both ends (summary by Tompson et al., 2010). Genetic Heterogeneity of Fibrochondrogenesis Fibrochondrogenesis-2 (FBCG2; 614524) is caused by mutation in the COL11A2 gene (120290) on chromosome 6p21.3.
Last Evaluated: Sep 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:33164453
Last Evaluated: Sep 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:33164453
Last Evaluated: Sep 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:33164453
Last Evaluated: Sep 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:33164453
Weissenbacher-Zweymüller syndrome is a condition that affects bone growth. It is characterized by skeletal abnormalities, hearing loss, and distinctive facial features. The features of this condition significantly overlap those of two similar conditions, otospondylomegaepiphyseal dysplasia (OSMED) and Stickler syndrome type III. All of these conditions are caused by mutations in the same gene, and in some cases, it can be difficult to tell them apart. Some researchers believe they represent a single disorder with a range of signs and symptoms.Infants born with Weissenbacher-Zweymüller syndrome are smaller than average because the bones in their arms and legs are unusually short. The thigh and upper arm bones are wider than usual at the ends (described as dumbbell-shaped), and the bones of the spine (vertebrae) may also be abnormally shaped. High-frequency hearing loss occurs in some cases. Distinctive facial features include wide-set protruding eyes, a small and upturned nose with a flat bridge, and a small lower jaw. Some affected infants are born with an opening in the roof of the mouth (a cleft palate).Most people with Weissenbacher-Zweymüller syndrome experience significant "catch-up" growth in the bones of the arms and legs during childhood. As a result, adults with this condition are not unusually short. However, affected adults still have other signs and symptoms of Weissenbacher-Zweymüller syndrome, including distinctive facial features and hearing loss.
Last Evaluated: Sep 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:33164453
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Sep 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:33164453
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:33164453
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
BUB1B
Variant:
c.573C>A
(p.Ser191=)
rsID: rs138809057
Ref Allele: C
Alt Allele: A
Freq: 0.0605%rare
CADD: 7.534
ClinVar Submissions (1)
Mosaic variegated aneuploidy (MVA) syndrome is a rare disorder in which some cells in the body have an abnormal number of chromosomes instead of the usual 46 chromosomes, a situation known as aneuploidy. Most commonly, cells have an extra chromosome, which is called trisomy, or are missing a chromosome, which is known as monosomy. In MVA syndrome, some cells are aneuploid and others have the normal number of chromosomes, which is a phenomenon known as mosaicism. Typically, at least one-quarter of cells in affected individuals have an abnormal number of chromosomes. Because the additional or missing chromosomes vary among the abnormal cells, the aneuploidy is described as variegated.In MVA syndrome, growth before birth is slow (intrauterine growth restriction). After birth, affected individuals continue to grow at a slow rate and are shorter than average. In addition, they typically have an unusually small head size (microcephaly). Another common feature of MVA syndrome is an increased risk of developing cancer in childhood. Cancers that occur most frequently in affected individuals include a cancer of muscle tissue called rhabdomyosarcoma, a form of kidney cancer known as Wilms tumor, and a cancer of the blood-forming tissue known as leukemia.Less commonly, people with MVA syndrome have eye abnormalities or distinctive facial features, such as a broad nasal bridge and low-set ears. Some affected individuals have brain abnormalities, the most common of which is called Dandy-Walker malformation. Intellectual disability, seizures, and other health problems can also occur in people with MVA syndrome.There are at least three types of MVA syndrome, each with a different genetic cause. Type 1 is the most common and displays the classic signs and symptoms described above. Type 2 appears to have slightly different signs and symptoms than type 1, although the small number of affected individuals makes it difficult to define its characteristic features. Individuals with MVA syndrome type 2 grow slowly before and after birth; however, their head size is typically normal. Some people with MVA syndrome type 2 have unusually short arms. Individuals with MVA syndrome type 2 do not seem to have an increased risk of cancer. Another form of MVA syndrome is characterized by a high risk of developing Wilms tumor. Individuals with this form may also have other signs and symptoms typical of MVA syndrome type 1.
Last Evaluated: Dec 04, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 15:40176665
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
SCN1B
Variant:
c.412G>A
(p.Val138Ile)
rsID: rs72558029
Ref Allele: G
Alt Allele: A
Freq: 0.0653%rare
CADD: 22.6
ClinVar Submissions (8)
Brugada syndrome is characterized by cardiac conduction abnormalities (ST-segment abnormalities in leads V1-V3 on ECG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and the sudden unexpected nocturnal death syndrome (SUNDS), a typical presentation in individuals from Southeast Asia. Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome.
Last Evaluated: Jul 20, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:35033703
Brugada syndrome is characterized by cardiac conduction abnormalities (ST-segment abnormalities in leads V1-V3 on ECG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and the sudden unexpected nocturnal death syndrome (SUNDS), a typical presentation in individuals from Southeast Asia. Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome.
Last Evaluated: Jul 20, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:35033703
Last Evaluated: Jul 20, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:35033703
Last Evaluated: Jul 20, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:35033703
Genetic epilepsy with febrile seizures plus (GEFS+) is a spectrum of seizure disorders of varying severity. GEFS+ is usually diagnosed in families whose members have a combination of febrile seizures, which are triggered by a high fever, and recurrent seizures (epilepsy) of other types, including seizures that are not related to fevers (afebrile seizures). The additional seizure types usually involve both sides of the brain (generalized seizures); however, seizures that involve only one side of the brain (partial seizures) occur in some affected individuals. The most common types of seizure in people with GEFS+ include myoclonic seizures, which cause involuntary muscle twitches; atonic seizures, which involve sudden episodes of weak muscle tone; and absence seizures, which cause loss of consciousness for short periods that appear as staring spells.The most common and mildest feature of the GEFS+ spectrum is simple febrile seizures, which begin in infancy and usually stop by age 5. When the febrile seizures continue after age 5 or other types of seizure develop, the condition is called febrile seizures plus (FS+). Seizures in FS+ usually end in early adolescence.A condition called Dravet syndrome (also known as severe myoclonic epilepsy of infancy or SMEI) is often considered part of the GEFS+ spectrum and is the most severe disorder in this group. Affected infants typically have prolonged seizures lasting several minutes (status epilepticus), which are triggered by fever. Other seizure types, including afebrile seizures, begin in early childhood. These types can include myoclonic or absence seizures. In Dravet syndrome, these seizures are difficult to control with medication, and they can worsen over time. A decline in brain function is also common in Dravet syndrome. Affected individuals usually develop normally in the first year of life, but then development stalls, and some affected children lose already-acquired skills (developmental regression). Many people with Dravet syndrome have difficulty coordinating movements (ataxia) and intellectual disability.Some people with GEFS+ have seizure disorders of intermediate severity that may not fit into the classical diagnosis of simple febrile seizures, FS+, or Dravet syndrome.Family members with GEFS+ may have different combinations of febrile seizures and epilepsy. For example, one affected family member may have only febrile seizures, while another also has myoclonic epilepsy. While GEFS+ is usually diagnosed in families, it can occur in individuals with no history of the condition in their family.
Last Evaluated: Jul 20, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:35033703
A condition that is characterized by episodes of fainting (SYNCOPE) and varying degree of ventricular arrhythmia as indicated by the prolonged QT interval. The inherited forms are caused by mutation of genes encoding cardiac ion channel proteins. The two major forms are ROMANO-WARD SYNDROME and JERVELL-LANGE NIELSEN SYNDROME.
Last Evaluated: Jul 20, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:35033703
Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder."
Last Evaluated: Jul 20, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:35033703
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 20, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:35033703
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 20, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:35033703
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
POMT1
Variant:
c.766-28A>G
rsID: rs187996836
Ref Allele: A
Alt Allele: G
Freq: 0.0741%rare
CADD: 3.416
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 01, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:131510232
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
SEC63
Variant:
c.340-12_340-7delGTTTTTinsCCC
rsID: rs1554237221
Ref Allele: AAAAAC
Alt Allele: A
Freq: 0.0749%rare
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 14, 2014
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:107921916
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
BRCA1
Variant:
c.441+36_441+50delCTTTTCTTTTTTTTT
rsID: rs1168113546
Ref Allele: AAAAAAAAAGAAAAG
Alt Allele: A
Freq: 0.0749%rare
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 25, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:43104072
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
PLEKHG5
Variant:
c.532G>A
(p.Gly178Arg)
rsID: rs143484278
Ref Allele: C
Alt Allele: T
Freq: 0.0765%rare
CADD: 9.07
ClinVar Submissions (3)
CMTRIC is an autosomal recessive peripheral neuropathy characterized by distal sensory impairment predominantly affecting the lower limbs and resulting in walking difficulties due to muscle weakness and atrophy. The upper limbs may also be affected. Electrophysiologic studies and sural nerve biopsy show mixed features of demyelinating and axonal neuropathy. The age at onset and the severity of the disease are variable (summary by Azzedine et al., 2013). For a discussion of genetic heterogeneity of autosomal recessive intermediate CMT, see CMTRIA (608340).
Last Evaluated: Jan 30, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:6474072
Last Evaluated: Jan 30, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:6474072
Last Evaluated: Jan 30, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:6474072
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 30, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:6474072
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
ABCB11
Variant:
c.1772A>G
(p.Asn591Ser)
rsID: rs11568367
Ref Allele: T
Alt Allele: C
Freq: 0.0796%rare
CADD: 24.1
ClinVar Submissions (3)
Progressive familial intrahepatic cholestasis (PFIC) is a disorder that causes progressive liver disease, which typically leads to liver failure. In people with PFIC, liver cells are less able to secrete a digestive fluid called bile. The buildup of bile in liver cells causes liver disease in affected individuals.Signs and symptoms of PFIC typically begin in infancy and are related to bile buildup and liver disease. Specifically, affected individuals experience severe itching, yellowing of the skin and whites of the eyes (jaundice), failure to gain weight and grow at the expected rate (failure to thrive), high blood pressure in the vein that supplies blood to the liver (portal hypertension), and an enlarged liver and spleen (hepatosplenomegaly).There are three known types of PFIC: PFIC1, PFIC2, and PFIC3. The types are also sometimes described as shortages of particular proteins needed for normal liver function. Each type has a different genetic cause.In addition to signs and symptoms related to liver disease, people with PFIC1 may have short stature, deafness, diarrhea, inflammation of the pancreas (pancreatitis), and low levels of fat-soluble vitamins (vitamins A, D, E, and K) in the blood. Affected individuals typically develop liver failure before adulthood.The signs and symptoms of PFIC2 are typically related to liver disease only; however, these signs and symptoms tend to be more severe than those experienced by people with PFIC1. People with PFIC2 often develop liver failure within the first few years of life. Additionally, affected individuals are at increased risk of developing a type of liver cancer called hepatocellular carcinoma.Most people with PFIC3 have signs and symptoms related to liver disease only. Signs and symptoms of PFIC3 usually do not appear until later in infancy or early childhood; rarely, people are diagnosed in early adulthood. Liver failure can occur in childhood or adulthood in people with PFIC3.
Last Evaluated: Jul 05, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:168970082
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 05, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:168970082
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
TBX1
Variant:
c.-39C>T
rsID: rs72646950
Ref Allele: C
Alt Allele: T
Freq: 0.0828%rare
CADD: 14
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 26, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 22:19759605
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
VPS13A
Variant:
c.2201G>A
(p.Ser734Asn)
rsID: rs117320408
Ref Allele: G
Alt Allele: A
Freq: 0.0868%rare
CADD: 11.6
ClinVar Submissions (2)
Chorea-acanthocytosis (ChAc) is characterized by a progressive movement disorder, cognitive and behavior changes, a myopathy that can be subclinical, and chronic hyperCKemia in serum. Although the disorder is named for acanthocytosis of the red blood cells, this feature is variable. The movement disorder is mostly limb chorea, but some individuals present with parkinsonism. Dystonia is common and affects the oral region and especially the tongue, causing dysarthria and serious dysphagia with resultant weight loss. Habitual tongue and lip biting are characteristic, as well as tongue protrusion dystonia. Progressive cognitive and behavioral changes resemble those in a frontal lobe syndrome. Seizures are observed in almost half of affected individuals and can be the initial manifestation. Myopathy results in progressive distal muscle wasting and weakness. Mean age of onset in ChAc is about 30 years, although ChAc can develop as early as the first decade or as late as the seventh decade. It runs a chronic progressive course and may lead to major disability within a few years. Life expectancy is reduced, with age of death ranging from 28 to 61 years.
Last Evaluated: Mar 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 9:77252265
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 9:77252265
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
MYBPC3
Variant:
c.2870C>G
(p.Thr957Ser)
rsID: rs193922380
Ref Allele: G
Alt Allele: C
Freq: 0.0916%rare
CADD: 15.39
ClinVar Submissions (12)
Last Evaluated: Apr 16, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 12
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:47335077
Hypertrophic cardiomyopathy (HCM) is typically defined by the presence of unexplained left ventricular hypertrophy (LVH). Such LVH occurs in a non-dilated ventricle in the absence of other cardiac or systemic disease capable of producing the observed magnitude of increased LV wall thickness, such as pressure overload (e.g., long-standing hypertension, aortic stenosis) or storage/infiltrative disorders (e.g., Fabry disease, amyloidosis). The clinical manifestations of HCM range from asymptomatic LVH to progressive heart failure to sudden cardiac death (SCD), and vary from individual to individual even within the same family. Common symptoms include shortness of breath (particularly with exertion), chest pain, palpitations, orthostasis, presyncope, and syncope. Most often the LVH of HCM becomes apparent during adolescence or young adulthood, although it may also develop late in life, in infancy, or in childhood.
Last Evaluated: Apr 16, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 12
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:47335077
A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.
Last Evaluated: Apr 16, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 12
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:47335077
Left ventricular noncompaction is a heart (cardiac) muscle disorder that occurs when the lower left chamber of the heart (left ventricle), which helps the heart pump blood, does not develop correctly. Instead of the muscle being smooth and firm, the cardiac muscle in the left ventricle is thick and appears spongy. The abnormal cardiac muscle is weak and has an impaired ability to pump blood because it either cannot completely contract or it cannot completely relax. For the heart to pump blood normally, cardiac muscle must contract and relax fully.Some individuals with left ventricular noncompaction experience no symptoms at all; others have heart problems that can include sudden cardiac death. Additional signs and symptoms include abnormal blood clots, irregular heart rhythm (arrhythmia), a sensation of fluttering or pounding in the chest (palpitations), extreme fatigue during exercise (exercise intolerance), shortness of breath (dyspnea), fainting (syncope), swelling of the legs (lymphedema), and trouble laying down flat. Some affected individuals have features of other heart defects. Left ventricular noncompaction can be diagnosed at any age, from birth to late adulthood. Approximately two-thirds of individuals with left ventricular noncompaction develop heart failure.
Last Evaluated: Apr 16, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 12
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:47335077
Hypertrophic cardiomyopathy (HCM) is typically defined by the presence of unexplained left ventricular hypertrophy (LVH). Such LVH occurs in a non-dilated ventricle in the absence of other cardiac or systemic disease capable of producing the observed magnitude of increased LV wall thickness, such as pressure overload (e.g., long-standing hypertension, aortic stenosis) or storage/infiltrative disorders (e.g., Fabry disease, amyloidosis). The clinical manifestations of HCM range from asymptomatic LVH to progressive heart failure to sudden cardiac death (SCD), and vary from individual to individual even within the same family. Common symptoms include shortness of breath (particularly with exertion), chest pain, palpitations, orthostasis, presyncope, and syncope. Most often the LVH of HCM becomes apparent during adolescence or young adulthood, although it may also develop late in life, in infancy, or in childhood.
Last Evaluated: Apr 16, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 12
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:47335077
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Apr 16, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 12
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:47335077
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 16, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 12
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:47335077
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Low clinical importance, Likely benign — Ehlermann et al. 2008 reported seeing this in one hypertrophic cardiomyopathy case in a screen of 158 patients, and not in 430 controls (they reported it as novel). Similarly, Rodr�guez-Garc�a et al. 2010 saw it once in 130 cases and not in 200 controls. However, ExAC data reports an allele frequency of 0.15% in Europeans � 1 in 330 carriers. Both reported findings are consistent with ExAC data (and not significantly different from it). If this variant played any causal role (even one with reduced, but notable penetrance), it would have been seen much more frequently in patients; as no such enrichment was found, the pathogenic hypothesis is strongly disproven.
Conflicting/Uncertain
Hetero
Gene:
UMOD
Variant:
c.425G>A
(p.Arg142Gln)
rsID: rs199835347
Ref Allele: C
Alt Allele: T
Freq: 0.094%rare
CADD: 4.952
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:20348876
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
ARSH
Variant:
c.396G>C
(p.Pro132=)
rsID: rs61746890
Ref Allele: G
Alt Allele: C
Freq: 0.1099%rare
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Sep 27, 2017
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: X:3015025
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Homo
Gene:
KLF11
Variant:
c.782C>T
(p.Pro261Leu)
rsID: rs148123124
Ref Allele: C
Alt Allele: T
Freq: 0.1131%rare
CADD: 20.9
ClinVar Submissions (3)
Maturity-onset diabetes of the young is an autosomal dominant form of diabetes typically occurring before 25 years of age and caused by primary insulin secretion defects. Despite its low prevalence, MODY is not a single entity but represents genetic, metabolic, and clinical heterogeneity (Vaxillaire and Froguel, 2008). Genetic Heterogeneity of MODY MODY1 (125850) is caused by heterozygous mutation in the hepatocyte nuclear factor-4-alpha gene (HNF4A; 600281) on chromosome 20. MODY2 (125851) is caused by heterozygous mutation in the glucokinase gene (GCK; 138079) on chromosome 7. MODY3 (600496) is caused by heterozygous mutation in the hepatocyte nuclear factor-1alpha gene (HNF1A; 142410) on chromosome 12q24.2. MODY4 (606392) is caused by heterozygous mutation in the pancreas/duodenum homeobox protein-1 gene (PDX1; 600733) on chromosome 13q12.1. MODY5 (137920) is caused by heterozygous mutation in the gene encoding hepatic transcription factor-2 (TCF2; 189907) on chromosome 17cen-q21.3. MODY6 (606394) is caused by heterozygous mutation in the NEUROD1 gene (601724) on chromosome 2q32. MODY7 (610508) is caused by heterozygous mutation in the KLF11 gene (603301) on chromosome 2p25. MODY8 (609812), or diabetes-pancreatic exocrine dysfunction syndrome, is caused by heterozygous mutation in the CEL gene (114840) on chromosome 9q34. MODY9 (612225) is caused by heterozygous mutation in the PAX4 gene (167413) on chromosome 7q32. MODY10 (613370) is caused by heterozygous mutation in the insulin gene (INS; 176730) on chromosome 11p15.5. MODY11 (613375) is caused by heterozygous mutation in the BLK gene (191305) on chromosome 8p23. MODY13 (616329) is caused by heterozygous mutation in the KCNJ11 gene (600937) on chromosome 11p15. MODY14 (616511) is caused by heterozygous mutation in the APPL1 gene (604299) on chromosome 3p14.
Last Evaluated: Feb 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:10048119
Diabetes mellitus caused by mutation(s) in a single gene, usually presenting in childhood or early adulthood.
Last Evaluated: Feb 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:10048119
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:10048119
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
IGF1R
Variant:
c.*4466G>C
rsID: rs184311472
Ref Allele: G
Alt Allele: C
Freq: 0.1274%rare
CADD: 10.96
ClinVar Submissions (1)
Patients with mutations in the receptor for insulin-like growth factor I show intrauterine growth retardation and postnatal growth failure, resulting in short stature and microcephaly. Other features may include delayed bone age, developmental delay, and dysmorphic features.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 15:98961908
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
ITGA2
Variant:
c.3154A>T
(p.Thr1052Ser)
rsID: rs150997093
Ref Allele: A
Alt Allele: T
Freq: 0.129%rare
CADD: 13.81
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:53083349
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
ASPM
Variant:
c.9254T>C
(p.Ile3085Thr)
rsID: rs138138436
Ref Allele: A
Alt Allele: G
Freq: 0.1306%rare
CADD: 7.616
ClinVar Submissions (4)
Last Evaluated: Oct 12, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:197093092
Autosomal recessive primary microcephaly-5 (MCPH5) is characterized by decreased occipitofrontal circumference (OFC), usually less than 3 standard deviations (SD) of the mean, present at birth and associated with mental retardation and speech delay. Other features may include short stature or mild seizures. MCPH5 is associated with a simplification of the cerebral cortical gyral pattern in some cases, which is considered within the phenotypic spectrum of primary microcephaly (review by Woods et al., 2005; Saadi et al., 2009; Passemard et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly (MCPH), see MCPH1 (251200).
Last Evaluated: Oct 12, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:197093092
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 12, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:197093092
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
ERCC4
Variant:
c.*3327A>G
rsID: rs535056033
Ref Allele: A
Alt Allele: G
Freq: 0.1338%rare
CADD: 3.767
ClinVar Submissions (1)
Xeroderma pigmentosum (XP) is characterized by: Sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure in ~60% of affected individuals), with marked freckle-like pigmentation of the face before age two years in most affected individuals; Sunlight-induced ocular involvement (photophobia, keratitis, atrophy of the skin of the lids); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma). Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 16:13951674
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
ABCB11
Variant:
c.1791G>T
(p.Val597=)
rsID: rs11568371
Ref Allele: C
Alt Allele: A
Freq: 0.1561%rare
CADD: 0.091
ClinVar Submissions (3)
Progressive familial intrahepatic cholestasis (PFIC) is a disorder that causes progressive liver disease, which typically leads to liver failure. In people with PFIC, liver cells are less able to secrete a digestive fluid called bile. The buildup of bile in liver cells causes liver disease in affected individuals.Signs and symptoms of PFIC typically begin in infancy and are related to bile buildup and liver disease. Specifically, affected individuals experience severe itching, yellowing of the skin and whites of the eyes (jaundice), failure to gain weight and grow at the expected rate (failure to thrive), high blood pressure in the vein that supplies blood to the liver (portal hypertension), and an enlarged liver and spleen (hepatosplenomegaly).There are three known types of PFIC: PFIC1, PFIC2, and PFIC3. The types are also sometimes described as shortages of particular proteins needed for normal liver function. Each type has a different genetic cause.In addition to signs and symptoms related to liver disease, people with PFIC1 may have short stature, deafness, diarrhea, inflammation of the pancreas (pancreatitis), and low levels of fat-soluble vitamins (vitamins A, D, E, and K) in the blood. Affected individuals typically develop liver failure before adulthood.The signs and symptoms of PFIC2 are typically related to liver disease only; however, these signs and symptoms tend to be more severe than those experienced by people with PFIC1. People with PFIC2 often develop liver failure within the first few years of life. Additionally, affected individuals are at increased risk of developing a type of liver cancer called hepatocellular carcinoma.Most people with PFIC3 have signs and symptoms related to liver disease only. Signs and symptoms of PFIC3 usually do not appear until later in infancy or early childhood; rarely, people are diagnosed in early adulthood. Liver failure can occur in childhood or adulthood in people with PFIC3.
Last Evaluated: Jul 05, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:168970063
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 05, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:168970063
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
HSPA1L
Variant:
c.802G>A
(p.Ala268Thr)
rsID: rs34620296
Ref Allele: C
Alt Allele: T
Freq: 0.1585%rare
CADD: 26.6
ClinVar Submissions (1)
Last Evaluated: Aug 06, 2016
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: association
Assembly: GRCh38
Chromosome/Position: 6:31811171
Hetero
Gene:
RAB3GAP1
Variant:
c.*404C>T
rsID: rs149483456
Ref Allele: C
Alt Allele: T
Freq: 0.1649%rare
CADD: 6.6
ClinVar Submissions (1)
Warburg Micro syndrome is a rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism (summary by Morris-Rosendahl et al., 2010). Genetic Heterogeneity of Warburg Micro Syndrome Warburg Micro syndrome-2 (WARBM2; 614225) is caused by mutation in the RAB3GAP2 gene (609275) on chromosome 1q41. WARBM3 (614222) is caused by mutation in the RAB18 gene (602207) on chromosome 10p12. WARBM4 (615663) is caused by mutation in the TBC1D20 gene (611663) on chromosome 20p13. See also Martsolf syndrome (212720), a clinically overlapping but milder autosomal recessive disorder caused by autosomal recessive mutation in the RAB3GAP2 gene. Handley et al. (2013) provided an overview of the disease variants identified in the RAB3GAP1, RAB3GAP2, and RAB18 genes, noting that a total of 144 families with WARBM and 9 families with Martsolf syndrome had been studied. Mutations were identified in RAB3GAP1 in 41% of cases, in RAB3GAP2 in 7% of cases, and in RAB18 in 5% of cases. Although RAB18 had not been linked to RAB3 pathways, Handley et al. (2013) stated that mutations in all 3 genes cause an indistinguishable phenotype, making it likely that there is some functional overlap.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:135169185
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Homo
Gene:
SCN3B
Variant:
c.*4390C>T
rsID: rs139934383
Ref Allele: G
Alt Allele: A
Freq: 0.1792%rare
CADD: 1.952
ClinVar Submissions (1)
Brugada syndrome is characterized by cardiac conduction abnormalities (ST-segment abnormalities in leads V1-V3 on ECG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and the sudden unexpected nocturnal death syndrome (SUNDS), a typical presentation in individuals from Southeast Asia. Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 11:123629409
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
PLCG2
Variant:
c.2011A>G
(p.Ile671Val)
rsID: rs150833842
Ref Allele: A
Alt Allele: G
Freq: 0.1824%rare
CADD: 13.6
ClinVar Submissions (2)
Familial cold autoinflammatory syndrome-2 is an autosomal dominant immune disorder characterized by the development of cutaneous urticaria, erythema, and pruritus in response to cold exposure. Affected individuals have variable additional immunologic defects, including antibody deficiency, decreased numbers of B cells, defective B cells, increased susceptibility to infection, and increased risk of autoimmune disorders (summary by Ombrello et al., 2012). For a discussion of genetic heterogeneity of FCAS, see FCAS1 (120100).
Last Evaluated: Nov 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:81912673
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Nov 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:81912673
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
KCNMA1
Variant:
c.*2183C>T
rsID: rs201067003
Ref Allele: G
Alt Allele: A
Freq: 0.2063%rare
CADD: 21.6
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 10:76885083
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
TNFRSF14
Variant:
c.305-653T>C
rsID: rs148507536
Ref Allele: T
Alt Allele: C
Freq: 0.2118%rare
CADD: 0.043
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 19, 2013
Review Status: no assertion provided
Number of Submitters: 1
Clinical Significance: not provided
Assembly: GRCh38
Chromosome/Position: 1:2559170
Hetero
Gene:
ITGA6
Variant:
c.2989-6C>T
rsID: rs147900066
Ref Allele: C
Alt Allele: T
Freq: 0.223%rare
CADD: 0.151
ClinVar Submissions (1)
Epidermolysis bullosa with pyloric atresia (EB-PA) is characterized by fragility of the skin and mucous membranes, manifested by blistering with little or no trauma; congenital pyloric atresia; and ureteral and renal anomalies (dysplastic/multicystic kidney, hydronephrosis/hydroureter, ureterocele, duplicated renal collecting system, absent bladder). The course of EB-PA is usually severe and often lethal in the neonatal period. Most affected children succumb as neonates; those who survive may have severe blistering with formation of granulation tissue on the skin around the mouth, nose, fingers, and toes, and internally around the trachea. However, some affected individuals have little or no blistering later in life. Additional features shared by EB-PA and the other major forms of EB include congenital localized absence of skin (aplasia cutis congenita) affecting the extremities and/or head, milia, nail dystrophy, scarring alopecia, hypotrichosis, contractures, and dilated cardiomyopathy.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:172497969
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
BLK
Variant:
c.713G>A
(p.Arg238Gln)
rsID: rs141865425
Ref Allele: G
Alt Allele: A
Freq: 0.262%rare
CADD: 28
ClinVar Submissions (4)
Maturity-onset diabetes of the young is an autosomal dominant form of diabetes typically occurring before 25 years of age and caused by primary insulin secretion defects. Despite its low prevalence, MODY is not a single entity but represents genetic, metabolic, and clinical heterogeneity (Vaxillaire and Froguel, 2008). Genetic Heterogeneity of MODY MODY1 (125850) is caused by heterozygous mutation in the hepatocyte nuclear factor-4-alpha gene (HNF4A; 600281) on chromosome 20. MODY2 (125851) is caused by heterozygous mutation in the glucokinase gene (GCK; 138079) on chromosome 7. MODY3 (600496) is caused by heterozygous mutation in the hepatocyte nuclear factor-1alpha gene (HNF1A; 142410) on chromosome 12q24.2. MODY4 (606392) is caused by heterozygous mutation in the pancreas/duodenum homeobox protein-1 gene (PDX1; 600733) on chromosome 13q12.1. MODY5 (137920) is caused by heterozygous mutation in the gene encoding hepatic transcription factor-2 (TCF2; 189907) on chromosome 17cen-q21.3. MODY6 (606394) is caused by heterozygous mutation in the NEUROD1 gene (601724) on chromosome 2q32. MODY7 (610508) is caused by heterozygous mutation in the KLF11 gene (603301) on chromosome 2p25. MODY8 (609812), or diabetes-pancreatic exocrine dysfunction syndrome, is caused by heterozygous mutation in the CEL gene (114840) on chromosome 9q34. MODY9 (612225) is caused by heterozygous mutation in the PAX4 gene (167413) on chromosome 7q32. MODY10 (613370) is caused by heterozygous mutation in the insulin gene (INS; 176730) on chromosome 11p15.5. MODY11 (613375) is caused by heterozygous mutation in the BLK gene (191305) on chromosome 8p23. MODY13 (616329) is caused by heterozygous mutation in the KCNJ11 gene (600937) on chromosome 11p15. MODY14 (616511) is caused by heterozygous mutation in the APPL1 gene (604299) on chromosome 3p14.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 8:11555425
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by production of autoantibodies against nuclear, cytoplasmic, and cell surface molecules that transcend organ-specific boundaries. Tissue deposition of antibodies or immune complexes induces inflammation and subsequent injury of multiple organs and finally results in clinical manifestations of SLE, including glomerulonephritis, dermatitis, thrombosis, vasculitis, seizures, and arthritis. Evidence strongly suggests the involvement of genetic components in SLE susceptibility (summary by Oishi et al., 2008). Genetic Heterogeneity of Systemic Lupus Erythematosus An autosomal recessive form of systemic lupus erythematosus (SLEB16; 614420) is caused by mutation in the DNASE1L3 gene (602244) on chromosome 3p14.3. See MAPPING and MOLECULAR GENETICS sections for a discussion of genetic heterogeneity of susceptibility to SLE.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 8:11555425
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 8:11555425
This individual has one copy of the genetic mutation, and because the condition(s) are autosomal dominant, they may manifest the condition rather than just being a carrier. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
DUOX2
Variant:
c.3759G>A
(p.Pro1253=)
rsID: rs140663764
Ref Allele: C
Alt Allele: T
Freq: 0.2811%rare
CADD: 0.234
ClinVar Submissions (1)
Congenital hypothyroidism is a partial or complete loss of function of the thyroid gland (hypothyroidism) that affects infants from birth (congenital). The thyroid gland is a butterfly-shaped tissue in the lower neck. It makes iodine-containing hormones that play an important role in regulating growth, brain development, and the rate of chemical reactions in the body (metabolism). People with congenital hypothyroidism have lower-than-normal levels of these important hormones.Congenital hypothyroidism occurs when the thyroid gland fails to develop or function properly. In 80 to 85 percent of cases, the thyroid gland is absent, severely reduced in size (hypoplastic), or abnormally located. These cases are classified as thyroid dysgenesis. In the remainder of cases, a normal-sized or enlarged thyroid gland (goiter) is present, but production of thyroid hormones is decreased or absent. Most of these cases occur when one of several steps in the hormone synthesis process is impaired; these cases are classified as thyroid dyshormonogenesis. Less commonly, reduction or absence of thyroid hormone production is caused by impaired stimulation of the production process (which is normally done by a structure at the base of the brain called the pituitary gland), even though the process itself is unimpaired. These cases are classified as central (or pituitary) hypothyroidism.Signs and symptoms of congenital hypothyroidism result from the shortage of thyroid hormones. Affected babies may show no features of the condition, although some babies with congenital hypothyroidism are less active and sleep more than normal. They may have difficulty feeding and experience constipation. If untreated, congenital hypothyroidism can lead to intellectual disability and slow growth. In the United States and many other countries, all hospitals test newborns for congenital hypothyroidism. If treatment begins in the first two weeks after birth, infants usually develop normally.Congenital hypothyroidism can also occur as part of syndromes that affect other organs and tissues in the body. These forms of the condition are described as syndromic. Some common forms of syndromic hypothyroidism include Pendred syndrome, Bamforth-Lazarus syndrome, and brain-lung-thyroid syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 15:45097326
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
FANCI
Variant:
c.*440G>T
rsID: rs1801377
Ref Allele: G
Alt Allele: T
Freq: 0.2827%rare
CADD: 3.803
ClinVar Submissions (1)
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract – are more common in individuals with FA.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 15:89316899
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
PSEN1
Variant:
c.*4030A>G
rsID: rs186752250
Ref Allele: A
Alt Allele: G
Freq: 0.2859%rare
CADD: 0.925
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 14:73223319
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 14:73223319
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
CUBN
Variant:
c.910G>A
(p.Glu304Lys)
rsID: rs78201384
Ref Allele: C
Alt Allele: T
Freq: 0.2986%rare
CADD: 16.51
ClinVar Submissions (1)
A disorder characterized by the presence of ANEMIA, abnormally large red blood cells (megalocytes or macrocytes), and MEGALOBLASTS.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 10:17111024
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
SPAST
Variant:
c.*2589T>G
rsID: rs149425698
Ref Allele: T
Alt Allele: G
Freq: 0.309%rare
CADD: 11.01
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:32157085
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
MCM4
Variant:
c.1209A>G
(p.Pro403=)
rsID: rs17287656
Ref Allele: A
Alt Allele: G
Freq: 0.313%rare
CADD: 6.239
ClinVar Submissions (1)
Immunodeficiency-54 is an autosomal recessive primary immunodeficiency characterized by severe intra- and extrauterine growth retardation, microcephaly, decreased numbers of natural killer (NK) cells, and recurrent viral infections, most often affecting the respiratory tract and leading to respiratory failure. Affected individuals also have adrenal insufficiency requiring corticosteroid replacement therapy and may have an increased susceptibility to cancer. Laboratory studies of patient cells showed a DNA repair defect (summary by Gineau et al., 2012).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:47969832
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
PRKDC
Variant:
c.9446G>A
(p.Gly3149Asp)
rsID: rs8178208
Ref Allele: C
Alt Allele: T
Freq: 0.3146%rare
CADD: 12.85
ClinVar Submissions (2)
Last Evaluated: Jan 03, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:47817561
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 03, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:47817561
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
KRTAP10-7;TSPEAR
Variant:
c.46G>A
(p.Gly16Ser)
rsID: rs200384147
Ref Allele: G
Alt Allele: A
Freq: 0.3186%rare
CADD: 8.221
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 24, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 21:44600667
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
A2ML1
Variant:
c.621T>C
(p.Gly207=)
rsID: rs145494834
Ref Allele: T
Alt Allele: C
Freq: 0.3257%rare
CADD: 14.42
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 20, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:8835644
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
MCM4
Variant:
c.858C>T
(p.Ser286=)
rsID: rs17334388
Ref Allele: C
Alt Allele: T
Freq: 0.3329%rare
CADD: 9.031
ClinVar Submissions (1)
Immunodeficiency-54 is an autosomal recessive primary immunodeficiency characterized by severe intra- and extrauterine growth retardation, microcephaly, decreased numbers of natural killer (NK) cells, and recurrent viral infections, most often affecting the respiratory tract and leading to respiratory failure. Affected individuals also have adrenal insufficiency requiring corticosteroid replacement therapy and may have an increased susceptibility to cancer. Laboratory studies of patient cells showed a DNA repair defect (summary by Gineau et al., 2012).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:47966212
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
COL11A2
Variant:
c.2520G>A
(p.Arg840=)
rsID: rs117237998
Ref Allele: C
Alt Allele: T
Freq: 0.3432%rare
CADD: 7.336
ClinVar Submissions (4)
Fibrochondrogenesis is a severe, autosomal recessive, short-limbed skeletal dysplasia clinically characterized by a flat midface with a small nose and anteverted nares, significant shortening of all limb segments but relatively normal hands and feet, and a small bell-shaped thorax with a protuberant abdomen. Radiographically, the long bones are short and have broad metaphyseal ends, giving them a dumb-bell shape. The vertebral bodies are flat and, on lateral view, have a distinctive pinched appearance, with a hypoplastic posterior end and a rounded anterior end. The ribs are typically short and wide and have metaphyseal cupping at both ends (summary by Tompson et al., 2010). Genetic Heterogeneity of Fibrochondrogenesis Fibrochondrogenesis-2 (FBCG2; 614524) is caused by mutation in the COL11A2 gene (120290) on chromosome 6p21.3.
Last Evaluated: Jun 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:33174020
Last Evaluated: Jun 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:33174020
Last Evaluated: Jun 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:33174020
Last Evaluated: Jun 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:33174020
Weissenbacher-Zweymüller syndrome is a condition that affects bone growth. It is characterized by skeletal abnormalities, hearing loss, and distinctive facial features. The features of this condition significantly overlap those of two similar conditions, otospondylomegaepiphyseal dysplasia (OSMED) and Stickler syndrome type III. All of these conditions are caused by mutations in the same gene, and in some cases, it can be difficult to tell them apart. Some researchers believe they represent a single disorder with a range of signs and symptoms.Infants born with Weissenbacher-Zweymüller syndrome are smaller than average because the bones in their arms and legs are unusually short. The thigh and upper arm bones are wider than usual at the ends (described as dumbbell-shaped), and the bones of the spine (vertebrae) may also be abnormally shaped. High-frequency hearing loss occurs in some cases. Distinctive facial features include wide-set protruding eyes, a small and upturned nose with a flat bridge, and a small lower jaw. Some affected infants are born with an opening in the roof of the mouth (a cleft palate).Most people with Weissenbacher-Zweymüller syndrome experience significant "catch-up" growth in the bones of the arms and legs during childhood. As a result, adults with this condition are not unusually short. However, affected adults still have other signs and symptoms of Weissenbacher-Zweymüller syndrome, including distinctive facial features and hearing loss.
Last Evaluated: Jun 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:33174020
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:33174020
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
COL11A2
Variant:
c.1972-16C>T
rsID: rs117435723
Ref Allele: G
Alt Allele: A
Freq: 0.3432%rare
CADD: 0.669
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 15, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:33177241
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
SEPT9
Variant:
c.*876C>T
rsID: rs3826284
Ref Allele: C
Alt Allele: T
Freq: 0.344%rare
CADD: 1.797
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:77499534
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
COL11A2
Variant:
c.4392+12C>T
rsID: rs117267045
Ref Allele: G
Alt Allele: A
Freq: 0.3568%rare
CADD: 0.451
ClinVar Submissions (3)
Fibrochondrogenesis is a severe, autosomal recessive, short-limbed skeletal dysplasia clinically characterized by a flat midface with a small nose and anteverted nares, significant shortening of all limb segments but relatively normal hands and feet, and a small bell-shaped thorax with a protuberant abdomen. Radiographically, the long bones are short and have broad metaphyseal ends, giving them a dumb-bell shape. The vertebral bodies are flat and, on lateral view, have a distinctive pinched appearance, with a hypoplastic posterior end and a rounded anterior end. The ribs are typically short and wide and have metaphyseal cupping at both ends (summary by Tompson et al., 2010). Genetic Heterogeneity of Fibrochondrogenesis Fibrochondrogenesis-2 (FBCG2; 614524) is caused by mutation in the COL11A2 gene (120290) on chromosome 6p21.3.
Last Evaluated: Jun 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:33166501
Last Evaluated: Jun 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:33166501
Last Evaluated: Jun 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:33166501
Last Evaluated: Jun 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:33166501
Weissenbacher-Zweymüller syndrome is a condition that affects bone growth. It is characterized by skeletal abnormalities, hearing loss, and distinctive facial features. The features of this condition significantly overlap those of two similar conditions, otospondylomegaepiphyseal dysplasia (OSMED) and Stickler syndrome type III. All of these conditions are caused by mutations in the same gene, and in some cases, it can be difficult to tell them apart. Some researchers believe they represent a single disorder with a range of signs and symptoms.Infants born with Weissenbacher-Zweymüller syndrome are smaller than average because the bones in their arms and legs are unusually short. The thigh and upper arm bones are wider than usual at the ends (described as dumbbell-shaped), and the bones of the spine (vertebrae) may also be abnormally shaped. High-frequency hearing loss occurs in some cases. Distinctive facial features include wide-set protruding eyes, a small and upturned nose with a flat bridge, and a small lower jaw. Some affected infants are born with an opening in the roof of the mouth (a cleft palate).Most people with Weissenbacher-Zweymüller syndrome experience significant "catch-up" growth in the bones of the arms and legs during childhood. As a result, adults with this condition are not unusually short. However, affected adults still have other signs and symptoms of Weissenbacher-Zweymüller syndrome, including distinctive facial features and hearing loss.
Last Evaluated: Jun 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:33166501
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:33166501
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
ITGA6
Variant:
c.*1459G>T
rsID: rs142884581
Ref Allele: G
Alt Allele: T
Freq: 0.36%rare
CADD: 2.637
ClinVar Submissions (1)
Epidermolysis bullosa with pyloric atresia (EB-PA) is characterized by fragility of the skin and mucous membranes, manifested by blistering with little or no trauma; congenital pyloric atresia; and ureteral and renal anomalies (dysplastic/multicystic kidney, hydronephrosis/hydroureter, ureterocele, duplicated renal collecting system, absent bladder). The course of EB-PA is usually severe and often lethal in the neonatal period. Most affected children succumb as neonates; those who survive may have severe blistering with formation of granulation tissue on the skin around the mouth, nose, fingers, and toes, and internally around the trachea. However, some affected individuals have little or no blistering later in life. Additional features shared by EB-PA and the other major forms of EB include congenital localized absence of skin (aplasia cutis congenita) affecting the extremities and/or head, milia, nail dystrophy, scarring alopecia, hypotrichosis, contractures, and dilated cardiomyopathy.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:172505527
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
NDUFA6
Variant:
c.322C>T
(p.His108Tyr)
rsID: rs113437301
Ref Allele: G
Alt Allele: A
Freq: 0.36%rare
CADD: 22.9
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 17, 2015
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 22:42086248
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
SLC25A20
Variant:
c.*359C>T
rsID: rs116681393
Ref Allele: G
Alt Allele: A
Freq: 0.3759%rare
CADD: 8.621
ClinVar Submissions (1)
Carnitine-acylcarnitine translocase deficiency is a rare autosomal recessive metabolic disorder of long-chain fatty acid oxidation. Metabolic consequences include hypoketotic hypoglycemia under fasting conditions, hyperammonemia, elevated creatine kinase and transaminases, dicarboxylic aciduria, very low free carnitine and abnormal acylcarnitine profile with marked elevation of the long-chain acylcarnitines. Clinical features include neurologic abnormalities, cardiomyopathy and arrhythmias, skeletal muscle damage, and liver dysfunction. Most patients become symptomatic in the neonatal period with a rapidly progressive deterioration and a high mortality rate. However, presentations at a later age with a milder phenotype have been reported (summary by Rubio-Gozalbo et al., 2004).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 3:48857351
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
F2
Variant:
c.1824C>T
(p.Arg608=)
rsID: rs3136532
Ref Allele: C
Alt Allele: T
Freq: 0.3767%rare
CADD: 17
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:46739363
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
TP63
Variant:
c.*1939T>G
rsID: rs567626735
Ref Allele: T
Alt Allele: G
Freq: 0.3854%rare
CADD: 4.613
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:189896441
A condition in which middle parts of the hands and/or feet (digits and meta-carpals and -tarsals) are missing giving a cleft appearance. The severity is very variable ranging from slightly hypoplastic 3rd toe/fingers over absent 2nd or 3rd toes/fingers as far as oligo- or monodactyl hands and/or feet.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:189896441
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:189896441
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
ITGA6
Variant:
c.2862G>C
(p.Ser954=)
rsID: rs61757097
Ref Allele: G
Alt Allele: C
Freq: 0.3974%rare
CADD: 0.025
ClinVar Submissions (1)
Epidermolysis bullosa with pyloric atresia (EB-PA) is characterized by fragility of the skin and mucous membranes, manifested by blistering with little or no trauma; congenital pyloric atresia; and ureteral and renal anomalies (dysplastic/multicystic kidney, hydronephrosis/hydroureter, ureterocele, duplicated renal collecting system, absent bladder). The course of EB-PA is usually severe and often lethal in the neonatal period. Most affected children succumb as neonates; those who survive may have severe blistering with formation of granulation tissue on the skin around the mouth, nose, fingers, and toes, and internally around the trachea. However, some affected individuals have little or no blistering later in life. Additional features shared by EB-PA and the other major forms of EB include congenital localized absence of skin (aplasia cutis congenita) affecting the extremities and/or head, milia, nail dystrophy, scarring alopecia, hypotrichosis, contractures, and dilated cardiomyopathy.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:172491304
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
SLCO1B1
Variant:
c.*46T>G
rsID: rs71581985
Ref Allele: T
Alt Allele: G
Freq: 0.4125%rare
CADD: 3.948
ClinVar Submissions (1)
Rotor syndrome is characterized by mild conjugated and unconjugated hyperbilirubinemia which usually begins shortly after birth or in childhood. Jaundice may be intermittent. Conjunctival icterus may be the only clinical manifestation.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 12:21239235
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
SNAP29
Variant:
c.*138C>T
rsID: rs375995790
Ref Allele: C
Alt Allele: T
Freq: 0.4253%rare
CADD: 9.002
ClinVar Submissions (1)
CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma) syndrome refers to a unique constellation of clinical manifestations including microcephaly, severe neurologic impairment, psychomotor retardation, failure to thrive, and facial dysmorphism, as well as palmoplantar keratoderma and late-onset ichthyosis. Brain magnetic resonance imaging (MRI) shows various degrees of cerebral dysgenesis including absence of corpus callosum and cortical dysplasia. The syndrome has been found to be uniformly fatal between the ages of 5 and 12 years (Fuchs-Telem et al., 2011).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 22:20887974
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
MYH2
Variant:
c.2908G>A
(p.Val970Ile)
rsID: rs143872329
Ref Allele: C
Alt Allele: T
Freq: 0.4277%rare
CADD: 24
ClinVar Submissions (3)
Proximal myopathy and ophthalmoplegia is a relatively mild muscle disorder characterized by childhood onset of symptoms. The disorder is either slowly progressive or nonprogressive, and affected individuals retain ambulation, although there is variable severity. MYPOP can show both autosomal dominant and autosomal recessive inheritance; the phenotype is similar in both forms (summary by Lossos et al., 2005 and Tajsharghi et al., 2014).
Last Evaluated: Feb 28, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:10529864
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 28, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:10529864
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 28, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:10529864
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
FAT4
Variant:
c.831G>A
(p.Ala277=)
rsID: rs142490028
Ref Allele: G
Alt Allele: A
Freq: 0.4285%rare
CADD: 14.89
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 09, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:125317242
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
DNAH5
Variant:
c.2253C>A
(p.Asn751Lys)
rsID: rs115004914
Ref Allele: G
Alt Allele: T
Freq: 0.43%rare
CADD: 11.49
ClinVar Submissions (5)
Primary ciliary dyskinesia (PCD) is associated with situs abnormalities, abnormal sperm motility, and abnormal ciliary structure and function that result in retention of mucus and bacteria in the respiratory tract leading to chronic otosinopulmonary disease. More than 75% of full-term neonates with PCD have "neonatal respiratory distress" requiring supplemental oxygen for days to weeks. Chronic airway infection, apparent in early childhood, results in bronchiectasis that is almost uniformly present in adulthood. Nasal congestion and sinus infections, apparent in early childhood, persist through adulthood. Chronic/recurrent ear infection, apparent in most young children, can be associated with transient or later irreversible hearing loss. Situs inversus totalis (mirror-image reversal of all visceral organs with no apparent physiologic consequences) is present in 40%-50% of individuals with PCD; heterotaxy (discordance of right and left patterns of ordinarily asymmetric structures that can be associated with significant malformations) is present in approximately 12%. Virtually all males with PCD are infertile as a result of abnormal sperm motility.
Last Evaluated: Nov 10, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 5:13900212
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 10, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 5:13900212
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
MYH8
Variant:
c.5350C>G
(p.Arg1784Gly)
rsID: rs141215006
Ref Allele: G
Alt Allele: C
Freq: 0.43%rare
CADD: 25.2
ClinVar Submissions (3)
Diseases that are caused by genetic mutations present during embryo or fetal development, although they may be observed later in life. The mutations may be inherited from a parent's genome or they may be acquired in utero.
Last Evaluated: Mar 11, 2015
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:10392944
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 11, 2015
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:10392944
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
DNAH5
Variant:
c.2053-23A>C
rsID: rs114717951
Ref Allele: T
Alt Allele: G
Freq: 0.4308%rare
CADD: 0.163
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:13900435
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
MYO5B
Variant:
c.*2293T>G
rsID: rs57818618
Ref Allele: A
Alt Allele: C
Freq: 0.4372%rare
CADD: 9.712
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 18:49824178
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
TTN
Variant:
c.37624G>A
(p.Asp12542Asn)
rsID: rs17354992
Ref Allele: C
Alt Allele: T
Freq: 0.4412%rare
CADD: 21.5
ClinVar Submissions (8)
Last Evaluated: Jan 09, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178621496
Last Evaluated: Jan 09, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178621496
Last Evaluated: Jan 09, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178621496
Udd distal myopathy is characterized by weakness of ankle dorsiflexion and inability to walk on the heels after age 35 years. Disease progression is slow and muscle weakness remains confined to the anterior tibial muscles. The long toe extensors become clinically involved after ten to 20 years, leading to foot drop and clumsiness when walking. In the mildest form, Udd distal myopathy can remain unnoticed even in the elderly.
Last Evaluated: Jan 09, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178621496
Hereditary myopathy with early respiratory failure (HMERF) is a slowly progressive myopathy that typically begins in the third to fifth decades of life. The usual presenting findings are gait disturbance relating to distal leg weakness or nocturnal respiratory symptoms due to respiratory muscle weakness. Weakness eventually generalizes and affects both proximal and distal muscles. Most affected individuals require walking aids within a few years of onset; some progress to wheelchair dependence and require nocturnal noninvasive ventilatory support. The disease course varies even among individuals within the same family: some remain ambulant until their 70s whereas others may require ventilator support in their 40s.
Last Evaluated: Jan 09, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178621496
A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.
Last Evaluated: Jan 09, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178621496
Last Evaluated: Jan 09, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178621496
Limb-girdle muscular dystrophy is a term for a group of diseases that cause weakness and wasting of the muscles in the arms and legs. The muscles most affected are those closest to the body (proximal muscles), specifically the muscles of the shoulders, upper arms, pelvic area, and thighs.The severity, age of onset, and features of limb-girdle muscle dystrophy vary among the many subtypes of this condition and may be inconsistent even within the same family. Signs and symptoms may first appear at any age and generally worsen with time, although in some cases they remain mild.In the early stages of limb-girdle muscular dystrophy, affected individuals may have an unusual walking gait, such as waddling or walking on the balls of their feet, and may also have difficulty running. They may need to use their arms to press themselves up from a squatting position because of their weak thigh muscles. As the condition progresses, people with limb-girdle muscular dystrophy may eventually require wheelchair assistance.Muscle wasting may cause changes in posture or in the appearance of the shoulder, back, and arm. In particular, weak shoulder muscles tend to make the shoulder blades (scapulae) "stick out" from the back, a sign known as scapular winging. Affected individuals may also have an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Some develop joint stiffness (contractures) that can restrict movement in their hips, knees, ankles, or elbows. Overgrowth (hypertrophy) of the calf muscles occurs in some people with limb-girdle muscular dystrophy.Weakening of the heart muscle (cardiomyopathy) occurs in some forms of limb-girdle muscular dystrophy. Some affected individuals experience mild to severe breathing problems related to the weakness of muscles needed for breathing. In some cases, the breathing problems are severe enough that affected individuals need to use a machine to help them breathe (mechanical ventilation).Intelligence is generally unaffected in limb-girdle muscular dystrophy; however, developmental delay and intellectual disability have been reported in rare forms of the disorder.
Last Evaluated: Jan 09, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178621496
Salih myopathy is characterized by muscle weakness (manifest during the neonatal period or in early infancy) and delayed motor development; children acquire independent walking between age 20 months and four years. In the first decade of life, global motor performances are stable or tend to improve. Moderate joint and neck contractures and spinal rigidity may start in the first decade but become more obvious in the second decade. Scoliosis develops after age 11 years. Cardiac dysfunction starts between ages five and 16 years, progresses rapidly, and leads to death between ages eight and 20 years, usually from heart rhythm disturbances.
Last Evaluated: Jan 09, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178621496
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 09, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178621496
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 09, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178621496
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
COL5A1
Variant:
c.5137-12C>T
rsID: rs191758714
Ref Allele: C
Alt Allele: T
Freq: 0.4428%rare
CADD: 0.306
ClinVar Submissions (4)
A heterogeneous group of disorders, some hereditary, others acquired, characterized by abnormal structure or function of one or more of the elements of connective tissue, i.e., collagen, elastin, or the mucopolysaccharides.
Last Evaluated: Nov 01, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:134834959
Ehlers-Danlos syndrome is a group of disorders that affect connective tissues supporting the skin, bones, blood vessels, and many other organs and tissues. Defects in connective tissues cause the signs and symptoms of these conditions, which range from mildly loose joints to life-threatening complications.The various forms of Ehlers-Danlos syndrome have been classified in several different ways. Originally, 11 forms of Ehlers-Danlos syndrome were named using Roman numerals to indicate the types (type I, type II, and so on). In 1997, researchers proposed a simpler classification (the Villefranche nomenclature) that reduced the number of types to six and gave them descriptive names based on their major features. In 2017, the classification was updated to include rare forms of Ehlers-Danlos syndrome that were discovered more recently. The 2017 classification describes 13 types of Ehlers-Danlos syndrome.An unusually large range of joint movement (hypermobility) occurs in most forms of Ehlers-Danlos syndrome, and it is a hallmark feature of the hypermobile type. Infants and children with hypermobility often have weak muscle tone (hypotonia), which can delay the development of motor skills such as sitting, standing, and walking. The loose joints are unstable and prone to dislocation and chronic pain. In the arthrochalasia type of Ehlers-Danlos syndrome, infants have hypermobility and dislocations of both hips at birth.Many people with the Ehlers-Danlos syndromes have soft, velvety skin that is highly stretchy (elastic) and fragile. Affected individuals tend to bruise easily, and some types of the condition also cause abnormal scarring. People with the classical form of Ehlers-Danlos syndrome experience wounds that split open with little bleeding and leave scars that widen over time to create characteristic "cigarette paper" scars. The dermatosparaxis type of the disorder is characterized by loose skin that sags and wrinkles, and extra (redundant) folds of skin may be present.Some forms of Ehlers-Danlos syndrome, notably the vascular type and to a lesser extent the kyphoscoliotic, classical, and classical-like types, can cause unpredictable tearing (rupture) of blood vessels, leading to internal bleeding and other potentially life-threatening complications. The vascular type of Ehlers-Danlos syndrome is also associated with an increased risk of organ rupture, including tearing of the intestine and rupture of the uterus during pregnancy.Other types of Ehlers-Danlos syndrome have additional signs and symptoms. The cardiac-valvular type causes severe problems with the valves that control the movement of blood through the heart. People with the kyphoscoliotic type experience severe curvature of the spine that worsens over time and can interfere with breathing by restricting lung expansion. A type of Ehlers-Danlos syndrome called brittle cornea syndrome is characterized by thinness of the clear covering of the eye (the cornea) and other eye abnormalities. The spondylodysplastic type features short stature and skeletal abnormalities such as abnormally curved (bowed) limbs. Abnormalities of muscles, including hypotonia and permanently bent joints (contractures), are among the characteristic signs of the musculocontractural and myopathic forms of Ehlers-Danlos syndrome. The periodontal type causes abnormalities of the teeth and gums.
Last Evaluated: Nov 01, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:134834959
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 01, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:134834959
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
NOTCH2
Variant:
c.3980A>G
(p.Asp1327Gly)
rsID: rs61752484
Ref Allele: T
Alt Allele: C
Freq: 0.4635%rare
CADD: 18.47
ClinVar Submissions (3)
Hajdu-Cheney syndrome is a rare autosomal dominant skeletal disorder characterized by short stature, coarse and dysmorphic facies, bowing of the long bones, and vertebral anomalies. Facial features include hypertelorism, bushy eyebrows, micrognathia, small mouth with dental anomalies, low-set ears, and short neck. There is progressive focal bone destruction, including acroosteolysis and generalized osteoporosis. Additional and variable features include hearing loss, renal cysts, and cardiovascular anomalies (summary by Ramos et al., 1998; Simpson et al., 2011; Isidor et al., 2011).
Last Evaluated: Apr 23, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:119926524
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 23, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:119926524
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
SUN1
Variant:
c.78-4C>T
rsID: rs145390365
Ref Allele: C
Alt Allele: T
Freq: 0.4643%rare
CADD: 0.29
ClinVar Submissions (1)
Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of joint contractures that begin in early childhood, slowly progressive muscle weakness and wasting initially in a humero-peroneal distribution that later extends to the scapular and pelvic girdle muscles, and cardiac involvement that may manifest as palpitations, presyncope and syncope, poor exercise tolerance, and congestive heart failure. Age of onset, severity, and progression of muscle and cardiac involvement demonstrate both inter- and intrafamilial variability. Clinical variability ranges from early onset with severe presentation in childhood to late onset with slow progression in adulthood. In general, joint contractures appear during the first two decades, followed by muscle weakness and wasting. Cardiac involvement usually occurs after the second decade.
Last Evaluated: Jul 10, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:838794
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
SUN1
Variant:
c.738G>T
(p.Trp246Cys)
rsID: rs142011077
Ref Allele: G
Alt Allele: T
Freq: 0.4683%rare
CADD: 23.1
ClinVar Submissions (1)
Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of joint contractures that begin in early childhood, slowly progressive muscle weakness and wasting initially in a humero-peroneal distribution that later extends to the scapular and pelvic girdle muscles, and cardiac involvement that may manifest as palpitations, presyncope and syncope, poor exercise tolerance, and congestive heart failure. Age of onset, severity, and progression of muscle and cardiac involvement demonstrate both inter- and intrafamilial variability. Clinical variability ranges from early onset with severe presentation in childhood to late onset with slow progression in adulthood. In general, joint contractures appear during the first two decades, followed by muscle weakness and wasting. Cardiac involvement usually occurs after the second decade.
Last Evaluated: Jul 10, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:851463
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
LHX3
Variant:
c.*185T>A
rsID: rs144976921
Ref Allele: A
Alt Allele: T
Freq: 0.4691%rare
CADD: 9.446
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:136197140
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
SCN9A
Variant:
c.*2662G>A
rsID: rs149873320
Ref Allele: C
Alt Allele: T
Freq: 0.4707%rare
CADD: 0.434
ClinVar Submissions (1)
A syndrome characterized by indifference to PAIN despite the ability to distinguish noxious from non-noxious stimuli. Absent corneal reflexes and INTELLECTUAL DISABILITY may be associated. Familial forms with autosomal recessive and autosomal dominant patterns of inheritance have been described. (Adams et al., Principles of Neurology, 6th ed, p1343)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:166196010
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:166196010
Genetic epilepsy with febrile seizures plus (GEFS+) is a spectrum of seizure disorders of varying severity. GEFS+ is usually diagnosed in families whose members have a combination of febrile seizures, which are triggered by a high fever, and recurrent seizures (epilepsy) of other types, including seizures that are not related to fevers (afebrile seizures). The additional seizure types usually involve both sides of the brain (generalized seizures); however, seizures that involve only one side of the brain (partial seizures) occur in some affected individuals. The most common types of seizure in people with GEFS+ include myoclonic seizures, which cause involuntary muscle twitches; atonic seizures, which involve sudden episodes of weak muscle tone; and absence seizures, which cause loss of consciousness for short periods that appear as staring spells.The most common and mildest feature of the GEFS+ spectrum is simple febrile seizures, which begin in infancy and usually stop by age 5. When the febrile seizures continue after age 5 or other types of seizure develop, the condition is called febrile seizures plus (FS+). Seizures in FS+ usually end in early adolescence.A condition called Dravet syndrome (also known as severe myoclonic epilepsy of infancy or SMEI) is often considered part of the GEFS+ spectrum and is the most severe disorder in this group. Affected infants typically have prolonged seizures lasting several minutes (status epilepticus), which are triggered by fever. Other seizure types, including afebrile seizures, begin in early childhood. These types can include myoclonic or absence seizures. In Dravet syndrome, these seizures are difficult to control with medication, and they can worsen over time. A decline in brain function is also common in Dravet syndrome. Affected individuals usually develop normally in the first year of life, but then development stalls, and some affected children lose already-acquired skills (developmental regression). Many people with Dravet syndrome have difficulty coordinating movements (ataxia) and intellectual disability.Some people with GEFS+ have seizure disorders of intermediate severity that may not fit into the classical diagnosis of simple febrile seizures, FS+, or Dravet syndrome.Family members with GEFS+ may have different combinations of febrile seizures and epilepsy. For example, one affected family member may have only febrile seizures, while another also has myoclonic epilepsy. While GEFS+ is usually diagnosed in families, it can occur in individuals with no history of the condition in their family.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:166196010
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:166196010
Paroxysmal extreme pain disorder, formerly known as familial rectal pain, is characterized by paroxysms of rectal, ocular, or submandibular pain with flushing. Onset is usually in the neonatal period or infancy (Fertleman et al., 2006).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:166196010
SCN1A-related seizure disorders encompass a spectrum that ranges from simple febrile seizures (FS) and generalized epilepsy with febrile seizures plus (GEFS+) at the mild end to Dravet syndrome and intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) at the severe end. Phenotypes with intractable seizures including Dravet syndrome (also known as severe myoclonic epilepsy in infancy [SMEI] or polymorphic myoclonic epilepsy in infancy [PMEI]) are usually associated with progressive dementia. Less commonly observed phenotypes include myoclonic-astatic epilepsy (MAE or Doose syndrome), Lennox-Gastaut syndrome (LGS), infantile spasms, and vaccine-related encephalopathy and seizures. The phenotype of SCN1A-related seizure disorders can vary even within the same family.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:166196010
Small fiber neuropathy is a condition characterized by severe pain attacks that typically begin in the feet or hands. As a person ages, the pain attacks can affect other regions. Some people initially experience a more generalized, whole-body pain. The attacks usually consist of pain described as stabbing or burning, or abnormal skin sensations such as tingling or itchiness. In some individuals, the pain is more severe during times of rest or at night. The signs and symptoms of small fiber neuropathy usually begin in adolescence to mid-adulthood.Individuals with small fiber neuropathy cannot feel pain that is concentrated in a very small area, such as the prick of a pin. However, they have an increased sensitivity to pain in general (hyperalgesia) and experience pain from stimulation that typically does not cause pain (hypoesthesia). People affected with this condition may also have a reduced ability to differentiate between hot and cold. However, in some individuals, the pain attacks are provoked by cold or warm triggers.Some affected individuals have urinary or bowel problems, episodes of rapid heartbeat (palpitations), dry eyes or mouth, or abnormal sweating. They can also experience a sharp drop in blood pressure upon standing (orthostatic hypotension), which can cause dizziness, blurred vision, or fainting.Small fiber neuropathy is considered a form of peripheral neuropathy because it affects the peripheral nervous system, which connects the brain and spinal cord to muscles and to cells that detect sensations such as touch, smell, and pain.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:166196010
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
THRB
Variant:
c.*107G>C
rsID: rs72619908
Ref Allele: C
Alt Allele: G
Freq: 0.4715%rare
CADD: 4.943
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:24122777
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
RYR2
Variant:
c.1292+20C>T
rsID: rs182050281
Ref Allele: C
Alt Allele: T
Freq: 0.4993%rare
CADD: 0.048
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 03, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:237445542
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
KIF1B
Variant:
c.*3341C>T
rsID: rs139210251
Ref Allele: C
Alt Allele: T
Freq: 0.5073%rare
CADD: 0.044
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:10379928
ALK-related neuroblastic tumor susceptibility is characterized by increased risk for neuroblastic tumors including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Neuroblastoma is a more malignant tumor and ganglioneuroma a more benign tumor. Depending on the histologic findings, ganglioneuroblastoma can behave in a more aggressive fashion, like neuroblastoma, or in a benign fashion, like ganglioneuroma. Preliminary data from the ten reported families with ALK-related neuroblastic tumor susceptibility suggest an overall penetrance of approximately 57% with the risk for neuroblastic tumor development highest in infancy and decreasing by late childhood.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:10379928
Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues distributed along the paravertebral axis from the base of the skull to the pelvis) and pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base and neck (referred to as head and neck PGL [HNPGL]) and sometimes in the upper mediastinum; approximately 95% of such tumors are nonsecretory. In contrast, sympathetic extra-adrenal paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically lead to catecholamine excess. Symptoms of PGL/PCC result from either mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for developing metastatic disease is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:10379928
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
ADAMTS2
Variant:
c.1629+9G>A
rsID: rs115550684
Ref Allele: C
Alt Allele: T
Freq: 0.5169%rare
CADD: 8.966
ClinVar Submissions (3)
Dermatosparaxis (meaning 'tearing of skin') is an autosomal recessive disorder of connective tissue resulting from deficiency of procollagen peptidase, an enzyme that aids in the processing of type I procollagen. The disorder and the responsible biochemical defect was first observed in cattle (Lapiere et al., 1971). Lapiere and Nusgens (1993) reviewed the discovery of dermatosparaxis in cattle, the elucidation of the disorder, its occurrence in other animals, and the delayed recognition of the disorder in the human.
Last Evaluated: Dec 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:179152133
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:179152133
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
DNAI1
Variant:
c.1604C>A
(p.Thr535Asn)
rsID: rs76334696
Ref Allele: C
Alt Allele: A
Freq: 0.5192%rare
CADD: 19.33
ClinVar Submissions (4)
Primary ciliary dyskinesia (PCD) is associated with situs abnormalities, abnormal sperm motility, and abnormal ciliary structure and function that result in retention of mucus and bacteria in the respiratory tract leading to chronic otosinopulmonary disease. More than 75% of full-term neonates with PCD have "neonatal respiratory distress" requiring supplemental oxygen for days to weeks. Chronic airway infection, apparent in early childhood, results in bronchiectasis that is almost uniformly present in adulthood. Nasal congestion and sinus infections, apparent in early childhood, persist through adulthood. Chronic/recurrent ear infection, apparent in most young children, can be associated with transient or later irreversible hearing loss. Situs inversus totalis (mirror-image reversal of all visceral organs with no apparent physiologic consequences) is present in 40%-50% of individuals with PCD; heterotaxy (discordance of right and left patterns of ordinarily asymmetric structures that can be associated with significant malformations) is present in approximately 12%. Virtually all males with PCD are infertile as a result of abnormal sperm motility.
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:34514428
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:34514428
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
CARD14
Variant:
c.2496C>T
(p.Leu832=)
rsID: rs139789664
Ref Allele: C
Alt Allele: T
Freq: 0.5232%rare
CADD: 8.333
ClinVar Submissions (1)
Pityriasis rubra pilaris is an uncommon skin disorder characterized by the appearance of keratotic follicular papules, well-demarcated salmon-colored erythematous plaques covered with fine powdery scales interspersed with distinct islands of uninvolved skin, and palmoplantar keratoderma. Most cases are sporadic, although up to 6.5% of PRP-affected individuals report a positive family history. The rare familial cases show autosomal dominant inheritance with incomplete penetrance and variable expression: the disorder is usually present at birth or appears during the first years of life and is characterized by prominent follicular hyperkeratosis, diffuse palmoplantar keratoderma, and erythema, with only a modest response to treatment (summary by Fuchs-Telem et al., 2012).
Last Evaluated: Jan 03, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:80205132
Last Evaluated: Jan 03, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:80205132
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
ABCC6
Variant:
c.3883-24G>A
rsID: rs59513011
Ref Allele: C
Alt Allele: T
Freq: 0.528%rare
CADD: 0.343
ClinVar Submissions (1)
Pseudoxanthoma elasticum (PXE) is a systemic disorder that affects the elastic tissue of the skin, the eye, and the cardiovascular and gastrointestinal systems. Individuals most commonly present with papules in the skin and/or with angioid streaks of the retina found on routine eye examination or associated with retinal hemorrhage. Rarely, individuals may present with vascular signs and symptoms, such as gastrointestinal bleeding, angina, or intermittent claudication. The most frequent cause of morbidity and disability in PXE is reduced vision from macular hemorrhage and disciform scarring of the macula. Most affected individuals live a normal life span.
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 16:16155055
This individual has one copy of the genetic mutation, and because it's autosomal recessive, they are likely a carrier rather than manifesting the condition. Interpretation of carrier status should be backed by thorough research.
Clinically Significant Pathogenic
Hetero
Gene:
NDUFA10
Variant:
c.-93G>T
rsID: rs577432343
Ref Allele: C
Alt Allele: A
Freq: 0.5376%rare
CADD: 4.562
ClinVar Submissions (1)
Leigh syndrome is a clinically and genetically heterogeneous disorder resulting from defective mitochondrial energy generation. It most commonly presents as a progressive and severe neurodegenerative disorder with onset within the first months or years of life, and may result in early death. Affected individuals usually show global developmental delay or developmental regression, hypotonia, ataxia, dystonia, and ophthalmologic abnormalities, such as nystagmus or optic atrophy. The neurologic features are associated with the classic findings of T2-weighted hyperintensities in the basal ganglia and/or brainstem on brain imaging. Leigh syndrome can also have detrimental multisystemic affects on the cardiac, hepatic, gastrointestinal, and renal organs. Biochemical studies in patients with Leigh syndrome tend to show increased lactate and abnormalities of mitochondrial oxidative phosphorylation. Thus, Leigh syndrome may be a clinical feature of a primary deficiency of any of the mitochondrial respiratory chain complexes: complex I deficiency (see 252010), complex II deficiency (see 252011), complex III deficiency (see 124000), complex IV deficiency (cytochrome c oxidase; see 220110), or complex V deficiency (see 604273) (summary by Lake et al., 2015). Genetic Heterogeneity of Leigh Syndrome Mutations in complex I genes include mitochondrial-encoded MTND2 (516001), MTND3 (516002), MTND5 (516005), and MTND6 (516006), the nuclear-encoded NDUFS1 (157655), NDUFS3 (603846), NDUFS4 (602694), NDUFS7 (601825), NDUFS8 (602141), NDUFA2 (602137), NDUFA9 (603834), NDUFA10 (603835), NDUFA12 (614530), NDUFAF6 (612392), and NDUFAF5 (612360). Mutation in the MTFMT gene (611766), which is involved in mitochondrial translation, has also been reported with complex I deficiency. A mutation has been found in a complex III gene: BCS1L (603647), which is involved in the assembly of complex III. Mutations in complex IV genes include mitochondrial-encoded MTCO3 (516050) and nuclear-encoded COX10 (602125), COX15 (603646), SCO2 (604272), SURF1 (185620), which is involved in the assembly of complex IV, TACO1 (612958), and PET100 (614770). A mutation has been found in a complex V gene: the mitochondrial-encoded MTATP6 (516060). Mutations in genes encoding mitochondrial tRNA proteins have also been identified in patients with Leigh syndrome: see MTTV (590105), MTTK (590060), MTTW (590095), and MTTL1 (590050). Leigh syndrome may also be caused by mutations in components of the pyruvate dehydrogenase complex (e.g., DLD, 238331 and PDHA1, 300502). The French Canadian (or Saguenay-Lac-Saint-Jean) type of Leigh syndrome with COX deficiency (LSFC; 220111) is caused by mutation in the LRPPRC gene (607544). Deficiency of coenzyme Q10 (607426) can present as Leigh syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:240025394
Isolated complex I deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders (McFarland et al., 2004; Kirby et al., 2004). It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome (see 256000), Leber hereditary optic neuropathy (535000), and some forms of Parkinson disease (see 556500) (Loeffen et al., 2000; Pitkanen et al., 1996; Robinson, 1998). Genetic Heterogeneity of Complex I Deficiency Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible (summary by Haack et al., 2012). However, the majority of cases are caused by mutations in nuclear-encoded genes (Loeffen et al., 2000; Triepels et al., 2001). Complex I deficiency resulting from mutation in nuclear-encoded genes include MC1DN1, caused by mutation in the NDUFS4 gene (602694); MC1DN2 (618222), caused by mutation in the NDUFS8 gene (602141); MC1DN3 (618224), caused by mutation in the NDUFS7 gene (601825); MC1DN4 (618225), caused by mutation in the NDUFV1 gene (161015); MC1DN5 (618226), caused by mutation in the NDUFS1 gene (157655); MC1DN6 (618228), caused by mutation in the NDUFS2 gene (602985); MC1DN7 (618229), caused by mutation in the NDUFV2 gene (600532); MC1DN8 (618230), caused by mutation in the NDUFS3 gene (603846); MC1DN9 (618232), caused by mutation in the NDUFS6 gene (603848); MC1DN10 (618233), caused by mutation in the NDUFAF2 gene (609653); MC1DN11 (618234), caused by mutation in the NDUFAF1 gene (606934); MC1DN12 (301020), caused by mutation in the NDUFA1 gene (300078); MC1DN13 (618235), caused by mutation in the NDUFA2 gene (602137); MC1DN14 (618236), caused by mutation in the NDUFA11 gene (612638); MC1DN15 (618237), caused by mutation in the NDUFAF4 gene (611776); MC1DN16 (618238), caused by mutation in the NDUFAF5 gene (612360); MC1DN17 (618239), caused by mutation in the NDUFAF6 gene (612392); MC1DN18 (618240), caused by mutation in the NDUFAF3 gene (612911); MC1DN19 (618241), caused by mutation in the FOXRED1 gene (613622); MC1DN20 (611126), caused by mutation in the ACAD9 gene (611103); MC1DN21 (618242), caused by mutation in the NUBPL gene (613621); MC1DN22 (618243), caused by mutation in the NDUFA10 gene (603835); MC1DN23 (618244), caused by mutation in the NDUFA12 gene (614530); MC1DN24 (618245), caused by mutation in the NDUFB9 gene (601445); MC1DN25 (618246), caused by mutation in the NDUFB3 gene (603839); MC1DN26 (618247), caused by mutation in the NDUFA9 gene (603834); MC1DN27 (618248), caused by mutation in the MTFMT gene (611766); MC1DN28 (618249), caused by mutation in the NDUFA13 gene (609435); MC1DN29 (618250), caused by mutation in the TMEM126B gene (615533); MC1DN30 (301021), caused by mutation in the NDUFB11 gene (300403); MC1DN31 (618251), caused by mutation in the TIMMDC1 gene (615534); MC1DN32 (618252), caused by mutation in the NDUFB8 gene (602140); and MC1DN33 (618253), caused by mutation in the NDUFA6 gene (602138). Complex I deficiency with mitochondrial inheritance has been associated with mutation in 6 mitochondrial-encoded components of complex I: MTND1 (516000), MTND2 (516001), MTND3 (516002), MTND4 (516003), MTND5 (516005), MTND6 (516006). Most of these patients have a phenotype of Leber hereditary optic neuropathy (LHON; 535000) or Leigh syndrome. Features of complex I deficiency may also be caused by mutation in other mitochondrial genes, including MTTS2 (590085).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:240025394
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
ALX4
Variant:
c.69G>C
(p.Pro23=)
rsID: rs115968657
Ref Allele: C
Alt Allele: G
Freq: 0.5503%rare
CADD: 18.09
ClinVar Submissions (1)
Enlarged parietal foramina is an inherited condition of impaired skull development. It is characterized by enlarged openings (foramina) in the parietal bones, which are the two bones that form the top and sides of the skull. This condition is due to incomplete bone formation (ossification) within the parietal bones. The openings are symmetrical and circular in shape, ranging in size from a few millimeters to several centimeters wide. Parietal foramina are a normal feature of fetal development, but typically they close before the baby is born, usually by the fifth month of pregnancy. However, in people with this condition, the parietal foramina remain open throughout life.The enlarged parietal foramina are soft to the touch due to the lack of bone at those areas of the skull. People with enlarged parietal foramina usually do not have any related health problems; however, scalp defects, seizures, and structural brain abnormalities have been noted in a small percentage of affected people. Pressure applied to the openings can lead to severe headaches, and individuals with this condition have an increased risk of brain damage or skull fractures if any trauma is experienced in the area of the openings.There are two forms of enlarged parietal foramina, called type 1 and type 2, which differ in their genetic cause.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:44309994
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
SCN9A
Variant:
c.*2323G>T
rsID: rs142172527
Ref Allele: C
Alt Allele: A
Freq: 0.5718%rare
CADD: 0.203
ClinVar Submissions (1)
A syndrome characterized by indifference to PAIN despite the ability to distinguish noxious from non-noxious stimuli. Absent corneal reflexes and INTELLECTUAL DISABILITY may be associated. Familial forms with autosomal recessive and autosomal dominant patterns of inheritance have been described. (Adams et al., Principles of Neurology, 6th ed, p1343)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:166196349
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:166196349
Genetic epilepsy with febrile seizures plus (GEFS+) is a spectrum of seizure disorders of varying severity. GEFS+ is usually diagnosed in families whose members have a combination of febrile seizures, which are triggered by a high fever, and recurrent seizures (epilepsy) of other types, including seizures that are not related to fevers (afebrile seizures). The additional seizure types usually involve both sides of the brain (generalized seizures); however, seizures that involve only one side of the brain (partial seizures) occur in some affected individuals. The most common types of seizure in people with GEFS+ include myoclonic seizures, which cause involuntary muscle twitches; atonic seizures, which involve sudden episodes of weak muscle tone; and absence seizures, which cause loss of consciousness for short periods that appear as staring spells.The most common and mildest feature of the GEFS+ spectrum is simple febrile seizures, which begin in infancy and usually stop by age 5. When the febrile seizures continue after age 5 or other types of seizure develop, the condition is called febrile seizures plus (FS+). Seizures in FS+ usually end in early adolescence.A condition called Dravet syndrome (also known as severe myoclonic epilepsy of infancy or SMEI) is often considered part of the GEFS+ spectrum and is the most severe disorder in this group. Affected infants typically have prolonged seizures lasting several minutes (status epilepticus), which are triggered by fever. Other seizure types, including afebrile seizures, begin in early childhood. These types can include myoclonic or absence seizures. In Dravet syndrome, these seizures are difficult to control with medication, and they can worsen over time. A decline in brain function is also common in Dravet syndrome. Affected individuals usually develop normally in the first year of life, but then development stalls, and some affected children lose already-acquired skills (developmental regression). Many people with Dravet syndrome have difficulty coordinating movements (ataxia) and intellectual disability.Some people with GEFS+ have seizure disorders of intermediate severity that may not fit into the classical diagnosis of simple febrile seizures, FS+, or Dravet syndrome.Family members with GEFS+ may have different combinations of febrile seizures and epilepsy. For example, one affected family member may have only febrile seizures, while another also has myoclonic epilepsy. While GEFS+ is usually diagnosed in families, it can occur in individuals with no history of the condition in their family.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:166196349
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:166196349
Paroxysmal extreme pain disorder, formerly known as familial rectal pain, is characterized by paroxysms of rectal, ocular, or submandibular pain with flushing. Onset is usually in the neonatal period or infancy (Fertleman et al., 2006).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:166196349
SCN1A-related seizure disorders encompass a spectrum that ranges from simple febrile seizures (FS) and generalized epilepsy with febrile seizures plus (GEFS+) at the mild end to Dravet syndrome and intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) at the severe end. Phenotypes with intractable seizures including Dravet syndrome (also known as severe myoclonic epilepsy in infancy [SMEI] or polymorphic myoclonic epilepsy in infancy [PMEI]) are usually associated with progressive dementia. Less commonly observed phenotypes include myoclonic-astatic epilepsy (MAE or Doose syndrome), Lennox-Gastaut syndrome (LGS), infantile spasms, and vaccine-related encephalopathy and seizures. The phenotype of SCN1A-related seizure disorders can vary even within the same family.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:166196349
Small fiber neuropathy is a condition characterized by severe pain attacks that typically begin in the feet or hands. As a person ages, the pain attacks can affect other regions. Some people initially experience a more generalized, whole-body pain. The attacks usually consist of pain described as stabbing or burning, or abnormal skin sensations such as tingling or itchiness. In some individuals, the pain is more severe during times of rest or at night. The signs and symptoms of small fiber neuropathy usually begin in adolescence to mid-adulthood.Individuals with small fiber neuropathy cannot feel pain that is concentrated in a very small area, such as the prick of a pin. However, they have an increased sensitivity to pain in general (hyperalgesia) and experience pain from stimulation that typically does not cause pain (hypoesthesia). People affected with this condition may also have a reduced ability to differentiate between hot and cold. However, in some individuals, the pain attacks are provoked by cold or warm triggers.Some affected individuals have urinary or bowel problems, episodes of rapid heartbeat (palpitations), dry eyes or mouth, or abnormal sweating. They can also experience a sharp drop in blood pressure upon standing (orthostatic hypotension), which can cause dizziness, blurred vision, or fainting.Small fiber neuropathy is considered a form of peripheral neuropathy because it affects the peripheral nervous system, which connects the brain and spinal cord to muscles and to cells that detect sensations such as touch, smell, and pain.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:166196349
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
TRIP11
Variant:
c.5086G>A
(p.Glu1696Lys)
rsID: rs80200454
Ref Allele: C
Alt Allele: T
Freq: 0.5853%rare
CADD: 23.1
ClinVar Submissions (2)
A rare group of disorders characterized by defective development of bones and cartilage.
Last Evaluated: Jan 30, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:91993883
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 30, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:91993883
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
TRIP11
Variant:
c.1904C>G
(p.Ser635Cys)
rsID: rs59635749
Ref Allele: G
Alt Allele: C
Freq: 0.5861%rare
CADD: 23.9
ClinVar Submissions (2)
A rare group of disorders characterized by defective development of bones and cartilage.
Last Evaluated: Jan 30, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:92006072
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 30, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:92006072
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
ELANE
Variant:
c.770C>T
(p.Pro257Leu)
rsID: rs17216663
Ref Allele: C
Alt Allele: T
Freq: 0.61%rare
CADD: 14.43
ClinVar Submissions (5)
ELANE-related neutropenia includes congenital neutropenia and cyclic neutropenia, both of which are primary hematologic disorders characterized by recurrent fever, skin and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, and pharyngitis), and cervical adenopathy. Infectious complications are generally more severe in congenital neutropenia than in cyclic neutropenia. In congenital neutropenia, omphalitis immediately after birth may be the first sign; in untreated children diarrhea, pneumonia, and deep abscesses in the liver, lungs, and subcutaneous tissues are common in the first year of life. After 15 years with granulocyte colony-stimulating factor treatment, the risk of developing myelodysplasia (MDS) or acute myelogenous leukemia (AML) is approximately 15%-25%. Cyclic neutropenia is usually diagnosed within the first year of life based on approximately three-week intervals of fever and oral ulcerations and regular oscillations of blood cell counts. Cellulitis, especially perianal cellulitis, is common during neutropenic periods. Between neutropenic periods, affected individuals are generally healthy. Symptoms improve in adulthood. Cyclic neutropenia is not associated with risk of malignancy or conversion to leukemia.
Last Evaluated: Jan 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:856130
ELANE-related neutropenia includes congenital neutropenia and cyclic neutropenia, both of which are primary hematologic disorders characterized by recurrent fever, skin and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, and pharyngitis), and cervical adenopathy. Infectious complications are generally more severe in congenital neutropenia than in cyclic neutropenia. In congenital neutropenia, omphalitis immediately after birth may be the first sign; in untreated children diarrhea, pneumonia, and deep abscesses in the liver, lungs, and subcutaneous tissues are common in the first year of life. After 15 years with granulocyte colony-stimulating factor treatment, the risk of developing myelodysplasia (MDS) or acute myelogenous leukemia (AML) is approximately 15%-25%. Cyclic neutropenia is usually diagnosed within the first year of life based on approximately three-week intervals of fever and oral ulcerations and regular oscillations of blood cell counts. Cellulitis, especially perianal cellulitis, is common during neutropenic periods. Between neutropenic periods, affected individuals are generally healthy. Symptoms improve in adulthood. Cyclic neutropenia is not associated with risk of malignancy or conversion to leukemia.
Last Evaluated: Jan 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:856130
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:856130
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:856130
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
VIL1
Variant:
c.684C>A
(p.His228Gln)
rsID: rs148353573
Ref Allele: C
Alt Allele: A
Freq: 0.6132%rare
CADD: 0.157
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 15, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:218429401
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
COL4A3
Variant:
c.4484A>G
(p.Gln1495Arg)
rsID: rs77964815
Ref Allele: A
Alt Allele: G
Freq: 0.6132%rare
CADD: 22.1
ClinVar Submissions (3)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 22, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:227308920
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
SGCA
Variant:
c.38-46G>C
rsID: rs142537375
Ref Allele: G
Alt Allele: C
Freq: 0.6156%rare
CADD: 2.767
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 10, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:50167322
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
ACTN4
Variant:
c.1998G>A
(p.Gln666=)
rsID: rs145474119
Ref Allele: G
Alt Allele: A
Freq: 0.6299%rare
CADD: 13.02
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:38724553
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
ANKRD1
Variant:
c.*319A>G
rsID: rs142439928
Ref Allele: T
Alt Allele: C
Freq: 0.6315%rare
CADD: 8.511
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 10:90912547
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
NPHP3
Variant:
c.3550G>A
(p.Ala1184Thr)
rsID: rs34391943
Ref Allele: C
Alt Allele: T
Freq: 0.6443%rare
CADD: 24.8
ClinVar Submissions (6)
A rare, lethal, autosomal recessive inherited syndrome characterized by pulmonary hypoplasia, central nervous system malformations, and hepatic malformations.
Last Evaluated: Nov 08, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:132684574
The nephronophthisis (NPH) phenotype is characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before age 30 years. Three age-based clinical subtypes are recongnized: infantile, juvenile, and adolescent/adult. Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia and facial dysmorphisms) or postnatally with renal manifestations that progress to ESRD before age 3 years. Juvenile NPH, the most prevalent subtype, typically presents with polydipsia and polyuria, growth retardation, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD). Hypertension is typically absent due to salt wasting. ESRD develops at a median age of 13 years. Ultrasound findings are increased echogenicity, reduced corticomedullary differentiation, and renal cysts (in 50% of affected individuals). Histologic findings include tubulointerstitial fibrosis, thickened and disrupted tubular basement membrane, sporadic corticomedullary cysts, and normal or reduced kidney size. Adolescent/ adult NPH is clinically similar to juvenile NPH, but ESRD develops at a median age of 19 years. Within a subtype inter- and intrafamilial variability in rate of progression to ESRD is considerable. Approximately 80%-90% of individuals with the NPH phenotype have no extrarenal features (i.e., they have isolated NPH); ~10%-20% have extrarenal manifestations that constitute a recognizable syndrome (e.g., Joubert syndrome, Bardet-Biedl syndrome, Jeune syndrome and related skeletal disorders, Meckel-Gruber syndrome, Senior-Løken syndrome, Leber congenital amaurosis, COACH syndrome, and oculomotor apraxia, Cogan type).
Last Evaluated: Nov 08, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:132684574
Last Evaluated: Nov 08, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:132684574
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Nov 08, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:132684574
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 08, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:132684574
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
PLIN1
Variant:
c.1043C>T
(p.Ser348Leu)
rsID: rs8179071
Ref Allele: G
Alt Allele: A
Freq: 0.6451%rare
CADD: 25.6
ClinVar Submissions (2)
Diabetes mellitus caused by mutation(s) in a single gene, usually presenting in childhood or early adulthood.
Last Evaluated: Aug 16, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 15:89667102
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 16, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 15:89667102
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
BAAT
Variant:
c.*895C>T
rsID: rs16936057
Ref Allele: G
Alt Allele: A
Freq: 0.6753%rare
CADD: 6.553
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:101361533
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
TRPV4
Variant:
c.2433G>C
(p.Ser811=)
rsID: rs34071623
Ref Allele: C
Alt Allele: G
Freq: 0.6753%rare
CADD: 2.302
ClinVar Submissions (4)
Last Evaluated: Dec 29, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:109784341
The TRPV4-associated disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within and between both groups is considerable. Bilateral progressive sensorineural hearing loss (SNHL) can occur in both. The three neuromuscular disorders (mildest to most severe): Charcot-Marie-Tooth disease type 2C (CMT2C). Scapuloperoneal spinal muscular atrophy (SPSMA). Congenital distal spinal muscular atrophy (CDSMA). The neuromuscular disorders are characterized by a progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six skeletal dysplasias: Mildest: Familial digital arthropathy-brachydactyly. Intermediate: Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Most severe: Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the TRPV4-associated disorders life span is normal; in the most severe it is shortened.
Last Evaluated: Dec 29, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:109784341
Last Evaluated: Dec 29, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:109784341
The TRPV4-associated disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within and between both groups is considerable. Bilateral progressive sensorineural hearing loss (SNHL) can occur in both. The three neuromuscular disorders (mildest to most severe): Charcot-Marie-Tooth disease type 2C (CMT2C). Scapuloperoneal spinal muscular atrophy (SPSMA). Congenital distal spinal muscular atrophy (CDSMA). The neuromuscular disorders are characterized by a progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six skeletal dysplasias: Mildest: Familial digital arthropathy-brachydactyly. Intermediate: Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Most severe: Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the TRPV4-associated disorders life span is normal; in the most severe it is shortened.
Last Evaluated: Dec 29, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:109784341
The TRPV4-associated disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within and between both groups is considerable. Bilateral progressive sensorineural hearing loss (SNHL) can occur in both. The three neuromuscular disorders (mildest to most severe): Charcot-Marie-Tooth disease type 2C (CMT2C). Scapuloperoneal spinal muscular atrophy (SPSMA). Congenital distal spinal muscular atrophy (CDSMA). The neuromuscular disorders are characterized by a progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six skeletal dysplasias: Mildest: Familial digital arthropathy-brachydactyly. Intermediate: Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Most severe: Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the TRPV4-associated disorders life span is normal; in the most severe it is shortened.
Last Evaluated: Dec 29, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:109784341
The TRPV4-associated disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within and between both groups is considerable. Bilateral progressive sensorineural hearing loss (SNHL) can occur in both. The three neuromuscular disorders (mildest to most severe): Charcot-Marie-Tooth disease type 2C (CMT2C). Scapuloperoneal spinal muscular atrophy (SPSMA). Congenital distal spinal muscular atrophy (CDSMA). The neuromuscular disorders are characterized by a progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six skeletal dysplasias: Mildest: Familial digital arthropathy-brachydactyly. Intermediate: Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Most severe: Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the TRPV4-associated disorders life span is normal; in the most severe it is shortened.
Last Evaluated: Dec 29, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:109784341
The Strudwick type of spondyloepimetaphyseal dysplasia (SEMD) is characterized by disproportionate short stature, pectus carinatum, and scoliosis, as well as dappled metaphyses (summary by Tiller et al., 1995).
Last Evaluated: Dec 29, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:109784341
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 29, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:109784341
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
LHX3
Variant:
c.*825C>A
rsID: rs3739470
Ref Allele: G
Alt Allele: T
Freq: 0.6777%rare
CADD: 8.295
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:136196500
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
SMC1A
Variant:
c.*5380G>A
rsID: rs186354950
Ref Allele: C
Alt Allele: T
Freq: 0.6833%rare
ClinVar Submissions (1)
Cornelia de Lange syndrome is a developmental disorder that affects many parts of the body. The features of this disorder vary widely among affected individuals and range from relatively mild to severe.Cornelia de Lange syndrome is characterized by slow growth before and after birth leading to short stature; intellectual disability that is usually moderate to severe; and abnormalities of bones in the arms, hands, and fingers. Most people with Cornelia de Lange syndrome also have distinctive facial features, including arched eyebrows that often meet in the middle (synophrys), long eyelashes, low-set ears, small and widely spaced teeth, and a small and upturned nose. Many affected individuals also have behavior problems similar to autism, a developmental condition that affects communication and social interaction.Additional signs and symptoms of Cornelia de Lange syndrome can include excessive body hair (hypertrichosis), an unusually small head (microcephaly), hearing loss, and problems with the digestive tract. Some people with this condition are born with an opening in the roof of the mouth called a cleft palate. Seizures, heart defects, and eye problems have also been reported in people with this condition.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: X:53374723
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Homo
Gene:
RAB3GAP1
Variant:
c.-53C>G
rsID: rs78560065
Ref Allele: C
Alt Allele: G
Freq: 0.6841%rare
CADD: 5.233
ClinVar Submissions (2)
Warburg Micro syndrome is a rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism (summary by Morris-Rosendahl et al., 2010). Genetic Heterogeneity of Warburg Micro Syndrome Warburg Micro syndrome-2 (WARBM2; 614225) is caused by mutation in the RAB3GAP2 gene (609275) on chromosome 1q41. WARBM3 (614222) is caused by mutation in the RAB18 gene (602207) on chromosome 10p12. WARBM4 (615663) is caused by mutation in the TBC1D20 gene (611663) on chromosome 20p13. See also Martsolf syndrome (212720), a clinically overlapping but milder autosomal recessive disorder caused by autosomal recessive mutation in the RAB3GAP2 gene. Handley et al. (2013) provided an overview of the disease variants identified in the RAB3GAP1, RAB3GAP2, and RAB18 genes, noting that a total of 144 families with WARBM and 9 families with Martsolf syndrome had been studied. Mutations were identified in RAB3GAP1 in 41% of cases, in RAB3GAP2 in 7% of cases, and in RAB18 in 5% of cases. Although RAB18 had not been linked to RAB3 pathways, Handley et al. (2013) stated that mutations in all 3 genes cause an indistinguishable phenotype, making it likely that there is some functional overlap.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:135052255
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:135052255
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Homo
Gene:
NPC2
Variant:
c.442-4A>C
rsID: rs114950106
Ref Allele: T
Alt Allele: G
Freq: 0.6984%rare
CADD: 5.042
ClinVar Submissions (4)
Niemann-Pick disease type C (NPC) is a lipid storage disease that can present in infants, children, or adults. Neonates can present with ascites and severe liver disease from infiltration of the liver and/or respiratory failure from infiltration of the lungs. Other infants, without liver or pulmonary disease, have hypotonia and developmental delay. The classic presentation occurs in mid-to-late childhood with the insidious onset of ataxia, vertical supranuclear gaze palsy (VSGP), and dementia. Dystonia and seizures are common. Dysarthria and dysphagia eventually become disabling, making oral feeding impossible; death usually occurs in the late second or third decade from aspiration pneumonia. Adults are more likely to present with dementia or psychiatric symptoms.
Last Evaluated: Dec 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:74480292
Niemann-Pick disease type C (NPC) is a lipid storage disease that can present in infants, children, or adults. Neonates can present with ascites and severe liver disease from infiltration of the liver and/or respiratory failure from infiltration of the lungs. Other infants, without liver or pulmonary disease, have hypotonia and developmental delay. The classic presentation occurs in mid-to-late childhood with the insidious onset of ataxia, vertical supranuclear gaze palsy (VSGP), and dementia. Dystonia and seizures are common. Dysarthria and dysphagia eventually become disabling, making oral feeding impossible; death usually occurs in the late second or third decade from aspiration pneumonia. Adults are more likely to present with dementia or psychiatric symptoms.
Last Evaluated: Dec 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:74480292
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:74480292
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:74480292
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
MC1R
Variant:
c.-356A>G
rsID: rs76337330
Ref Allele: A
Alt Allele: G
Freq: 0.7335%rare
CADD: 9.053
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 16:89918903
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
RFT1
Variant:
c.*1533G>A
rsID: rs139197209
Ref Allele: C
Alt Allele: T
Freq: 0.7645%rare
CADD: 3.652
ClinVar Submissions (1)
A genetically heterogeneous group of heritable disorders resulting from defects in protein N-glycosylation.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:53090370
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
AXIN1
Variant:
c.2186+7C>T
rsID: rs189357878
Ref Allele: G
Alt Allele: A
Freq: 0.7653%rare
CADD: 0.635
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Sep 27, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 16:293481
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
RFT1
Variant:
c.*2655T>C
rsID: rs148022607
Ref Allele: A
Alt Allele: G
Freq: 0.7685%rare
CADD: 0.879
ClinVar Submissions (1)
A genetically heterogeneous group of heritable disorders resulting from defects in protein N-glycosylation.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:53089248
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
AKR1D1
Variant:
c.*1139G>C
rsID: rs566511122
Ref Allele: G
Alt Allele: C
Freq: 0.798%rare
CADD: 1.892
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:138117801
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
INVS
Variant:
c.-155C>T
rsID: rs62577237
Ref Allele: C
Alt Allele: T
Freq: 0.7988%rare
CADD: 7.278
ClinVar Submissions (1)
The nephronophthisis (NPH) phenotype is characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before age 30 years. Three age-based clinical subtypes are recongnized: infantile, juvenile, and adolescent/adult. Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia and facial dysmorphisms) or postnatally with renal manifestations that progress to ESRD before age 3 years. Juvenile NPH, the most prevalent subtype, typically presents with polydipsia and polyuria, growth retardation, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD). Hypertension is typically absent due to salt wasting. ESRD develops at a median age of 13 years. Ultrasound findings are increased echogenicity, reduced corticomedullary differentiation, and renal cysts (in 50% of affected individuals). Histologic findings include tubulointerstitial fibrosis, thickened and disrupted tubular basement membrane, sporadic corticomedullary cysts, and normal or reduced kidney size. Adolescent/ adult NPH is clinically similar to juvenile NPH, but ESRD develops at a median age of 19 years. Within a subtype inter- and intrafamilial variability in rate of progression to ESRD is considerable. Approximately 80%-90% of individuals with the NPH phenotype have no extrarenal features (i.e., they have isolated NPH); ~10%-20% have extrarenal manifestations that constitute a recognizable syndrome (e.g., Joubert syndrome, Bardet-Biedl syndrome, Jeune syndrome and related skeletal disorders, Meckel-Gruber syndrome, Senior-Løken syndrome, Leber congenital amaurosis, COACH syndrome, and oculomotor apraxia, Cogan type).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 9:100099286
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
TTN
Variant:
c.45488T>C
(p.Ile15163Thr)
rsID: rs72646809
Ref Allele: A
Alt Allele: G
Freq: 0.8012%rare
CADD: 25.7
ClinVar Submissions (7)
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178607496
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178607496
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178607496
Udd distal myopathy is characterized by weakness of ankle dorsiflexion and inability to walk on the heels after age 35 years. Disease progression is slow and muscle weakness remains confined to the anterior tibial muscles. The long toe extensors become clinically involved after ten to 20 years, leading to foot drop and clumsiness when walking. In the mildest form, Udd distal myopathy can remain unnoticed even in the elderly.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178607496
Hereditary myopathy with early respiratory failure (HMERF) is a slowly progressive myopathy that typically begins in the third to fifth decades of life. The usual presenting findings are gait disturbance relating to distal leg weakness or nocturnal respiratory symptoms due to respiratory muscle weakness. Weakness eventually generalizes and affects both proximal and distal muscles. Most affected individuals require walking aids within a few years of onset; some progress to wheelchair dependence and require nocturnal noninvasive ventilatory support. The disease course varies even among individuals within the same family: some remain ambulant until their 70s whereas others may require ventilator support in their 40s.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178607496
A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178607496
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178607496
Limb-girdle muscular dystrophy is a term for a group of diseases that cause weakness and wasting of the muscles in the arms and legs. The muscles most affected are those closest to the body (proximal muscles), specifically the muscles of the shoulders, upper arms, pelvic area, and thighs.The severity, age of onset, and features of limb-girdle muscle dystrophy vary among the many subtypes of this condition and may be inconsistent even within the same family. Signs and symptoms may first appear at any age and generally worsen with time, although in some cases they remain mild.In the early stages of limb-girdle muscular dystrophy, affected individuals may have an unusual walking gait, such as waddling or walking on the balls of their feet, and may also have difficulty running. They may need to use their arms to press themselves up from a squatting position because of their weak thigh muscles. As the condition progresses, people with limb-girdle muscular dystrophy may eventually require wheelchair assistance.Muscle wasting may cause changes in posture or in the appearance of the shoulder, back, and arm. In particular, weak shoulder muscles tend to make the shoulder blades (scapulae) "stick out" from the back, a sign known as scapular winging. Affected individuals may also have an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Some develop joint stiffness (contractures) that can restrict movement in their hips, knees, ankles, or elbows. Overgrowth (hypertrophy) of the calf muscles occurs in some people with limb-girdle muscular dystrophy.Weakening of the heart muscle (cardiomyopathy) occurs in some forms of limb-girdle muscular dystrophy. Some affected individuals experience mild to severe breathing problems related to the weakness of muscles needed for breathing. In some cases, the breathing problems are severe enough that affected individuals need to use a machine to help them breathe (mechanical ventilation).Intelligence is generally unaffected in limb-girdle muscular dystrophy; however, developmental delay and intellectual disability have been reported in rare forms of the disorder.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178607496
Salih myopathy is characterized by muscle weakness (manifest during the neonatal period or in early infancy) and delayed motor development; children acquire independent walking between age 20 months and four years. In the first decade of life, global motor performances are stable or tend to improve. Moderate joint and neck contractures and spinal rigidity may start in the first decade but become more obvious in the second decade. Scoliosis develops after age 11 years. Cardiac dysfunction starts between ages five and 16 years, progresses rapidly, and leads to death between ages eight and 20 years, usually from heart rhythm disturbances.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178607496
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178607496
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
TSEN54
Variant:
c.1328C>G
(p.Ser443Cys)
rsID: rs150169668
Ref Allele: C
Alt Allele: G
Freq: 0.8059%rare
CADD: 23.1
ClinVar Submissions (5)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 20, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:75523677
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 20, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:75523677
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
SLC20A2
Variant:
c.1008C>T
(p.His336=)
rsID: rs111553899
Ref Allele: G
Alt Allele: A
Freq: 0.8123%rare
CADD: 0.23
ClinVar Submissions (3)
Primary familial brain calcification (PFBC) is a neurodegenerative disorder with characteristic calcium deposits in the basal ganglia and other brain areas visualized on neuroimaging. Most affected individuals are in good health during childhood and young adulthood and typically present in the fourth to fifth decade with a gradually progressive movement disorder and neuropsychiatric symptoms. The movement disorder first manifests as clumsiness, fatigability, unsteady gait, slow or slurred speech, dysphagia, involuntary movements, or muscle cramping. Neuropsychiatric symptoms, often the first or most prominent manifestations, range from mild difficulty with concentration and memory to changes in personality and/or behavior, to psychosis and dementia. Seizures of various types occur frequently, some individuals experience chronic headache and vertigo; urinary urgency or incontinence may be present.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 8:42437504
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
OPA1
Variant:
c.1884A>G
(p.Val628=)
rsID: rs73069703
Ref Allele: A
Alt Allele: G
Freq: 0.8322%rare
CADD: 5.119
ClinVar Submissions (5)
Last Evaluated: Jul 17, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:193654898
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 17, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:193654898
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 17, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:193654898
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
OPA1
Variant:
c.2796C>T
(p.Arg932=)
rsID: rs35540805
Ref Allele: C
Alt Allele: T
Freq: 0.837%rare
CADD: 0.952
ClinVar Submissions (5)
Last Evaluated: Jun 25, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:193667258
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 25, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:193667258
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 25, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:193667258
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
XPNPEP3
Variant:
c.*809C>A
rsID: rs57486044
Ref Allele: C
Alt Allele: A
Freq: 0.8569%rare
CADD: 1.564
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 22:40927244
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
GALC
Variant:
c.1302C>T
(p.Ser434=)
rsID: rs3213918
Ref Allele: G
Alt Allele: A
Freq: 0.8689%rare
CADD: 1.33
ClinVar Submissions (5)
Krabbe disease comprises a spectrum ranging from infantile-onset disease (i.e., onset of extreme irritability, spasticity, and developmental delay before age 12 months) to later-onset disease (i.e., onset of manifestations after age 12 months and as late as the seventh decade). Although historically 85%-90% of symptomatic individuals with Krabbe disease diagnosed by enzyme activity alone have infantile-onset Krabbe disease and 10%-15% have later-onset Krabbe disease, the experience with newborn screening (NBS) suggests that the proportion of individuals with possible later-onset Krabbe disease is higher than previously thought. Infantile-onset Krabbe disease is characterized by normal development in the first few months followed by rapid severe neurologic deterioration; the average age of death is 24 months (range 8 months to 9 years). Later-onset Krabbe disease is much more variable in its presentation and disease course.
Last Evaluated: Dec 05, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:87949881
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 05, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:87949881
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 05, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:87949881
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
DRC1
Variant:
c.1067C>T
(p.Ala356Val)
rsID: rs78892546
Ref Allele: C
Alt Allele: T
Freq: 0.8712%rare
CADD: 14.46
ClinVar Submissions (1)
Primary ciliary dyskinesia (PCD) is associated with situs abnormalities, abnormal sperm motility, and abnormal ciliary structure and function that result in retention of mucus and bacteria in the respiratory tract leading to chronic otosinopulmonary disease. More than 75% of full-term neonates with PCD have "neonatal respiratory distress" requiring supplemental oxygen for days to weeks. Chronic airway infection, apparent in early childhood, results in bronchiectasis that is almost uniformly present in adulthood. Nasal congestion and sinus infections, apparent in early childhood, persist through adulthood. Chronic/recurrent ear infection, apparent in most young children, can be associated with transient or later irreversible hearing loss. Situs inversus totalis (mirror-image reversal of all visceral organs with no apparent physiologic consequences) is present in 40%-50% of individuals with PCD; heterotaxy (discordance of right and left patterns of ordinarily asymmetric structures that can be associated with significant malformations) is present in approximately 12%. Virtually all males with PCD are infertile as a result of abnormal sperm motility.
Last Evaluated: Jul 20, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:26444260
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
NPHP3
Variant:
c.154G>A
(p.Ala52Thr)
rsID: rs145643112
Ref Allele: C
Alt Allele: T
Freq: 0.9087%rare
CADD: 16.26
ClinVar Submissions (6)
The nephronophthisis (NPH) phenotype is characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before age 30 years. Three age-based clinical subtypes are recongnized: infantile, juvenile, and adolescent/adult. Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia and facial dysmorphisms) or postnatally with renal manifestations that progress to ESRD before age 3 years. Juvenile NPH, the most prevalent subtype, typically presents with polydipsia and polyuria, growth retardation, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD). Hypertension is typically absent due to salt wasting. ESRD develops at a median age of 13 years. Ultrasound findings are increased echogenicity, reduced corticomedullary differentiation, and renal cysts (in 50% of affected individuals). Histologic findings include tubulointerstitial fibrosis, thickened and disrupted tubular basement membrane, sporadic corticomedullary cysts, and normal or reduced kidney size. Adolescent/ adult NPH is clinically similar to juvenile NPH, but ESRD develops at a median age of 19 years. Within a subtype inter- and intrafamilial variability in rate of progression to ESRD is considerable. Approximately 80%-90% of individuals with the NPH phenotype have no extrarenal features (i.e., they have isolated NPH); ~10%-20% have extrarenal manifestations that constitute a recognizable syndrome (e.g., Joubert syndrome, Bardet-Biedl syndrome, Jeune syndrome and related skeletal disorders, Meckel-Gruber syndrome, Senior-Løken syndrome, Leber congenital amaurosis, COACH syndrome, and oculomotor apraxia, Cogan type).
Last Evaluated: Sep 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:132722202
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Sep 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:132722202
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:132722202
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
HSPG2
Variant:
c.1999-13C>T
rsID: rs77828146
Ref Allele: G
Alt Allele: A
Freq: 0.9533%rare
CADD: 4.527
ClinVar Submissions (1)
A rare genetic primary bone dysplasia and lethal form of neonatal short-limbed dwarfism, with characteristics of anisospondyly, severe short stature and limb shortening, metaphyseal flaring and distinct dysmorphic features (flat facial appearance, abnormal ears, short neck, narrow thorax). Additional features may include other skeletal findings (for example joint contractures, bowed limbs, talipes equinovarus) and urogenital and cardiovascular abnormalities.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:21880572
Schwartz-Jampel syndrome is a rare condition characterized by permanent muscle stiffness (myotonia) and bone abnormalities known as chondrodysplasia. The signs and symptoms of this condition become apparent sometime after birth, usually in early childhood. Either muscle stiffness or chondrodysplasia can appear first. The muscle and bone abnormalities worsen in childhood, although most affected individuals have a normal lifespan. The specific features of Schwartz-Jampel syndrome vary widely.Myotonia involves continuous tensing (contraction) of muscles used for movement (skeletal muscles) throughout the body. This sustained muscle contraction causes stiffness that interferes with eating, sitting, walking, and other movements. Sustained contraction of muscles in the face leads to a fixed, "mask-like" facial expression with narrow eye openings (blepharophimosis) and pursed lips. This facial appearance is very specific to Schwartz-Jampel syndrome. Affected individuals may also be nearsighted and experience abnormal blinking or spasms of the eyelids (blepharospasm).Chondrodysplasia affects the development of the skeleton, particularly the long bones in the arms and legs and the bones of the hips. These bones are shortened and unusually wide at the ends, so affected individuals have short stature. The long bones may also be abnormally curved (bowed). Other bone abnormalities associated with Schwartz-Jampel syndrome include a protruding chest (pectus carinatum), abnormal curvature of the spine, flattened bones of the spine (platyspondyly), and joint abnormalities called contractures that further restrict movement.Researchers originally described two types of Schwartz-Jampel syndrome. Type 1 has the signs and symptoms described above, while type 2 has more severe bone abnormalities and other health problems and is usually life-threatening in early infancy. Researchers have since discovered that the condition they thought was Schwartz-Jampel syndrome type 2 is actually part of another disorder, Stüve-Wiedemann syndrome, which is caused by mutations in a different gene. They have recommended that the designation Schwartz-Jampel syndrome type 2 no longer be used.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:21880572
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
OTX2
Variant:
c.97+12C>T
rsID: rs28757218
Ref Allele: G
Alt Allele: A
Freq: 0.966%rare
CADD: 10.79
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 14:56805348
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 14:56805348
A group of disorders involving predominantly the posterior portion of the ocular fundus, due to degeneration in the sensory layer of the RETINA; RETINAL PIGMENT EPITHELIUM; BRUCH MEMBRANE; CHOROID; or a combination of these tissues.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 14:56805348
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 14:56805348
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
CRYGC
Variant:
c.143G>A
(p.Arg48His)
rsID: rs61751949
Ref Allele: C
Alt Allele: T
Freq: 0.97%rare
CADD: 20.3
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 29, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:208129550
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
SNTA1
Variant:
c.828G>A
(p.Lys276=)
rsID: rs35938843
Ref Allele: C
Alt Allele: T
Freq: 0.9859%rare
CADD: 8.164
ClinVar Submissions (3)
Last Evaluated: Jul 10, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 20:33412656
A condition that is characterized by episodes of fainting (SYNCOPE) and varying degree of ventricular arrhythmia as indicated by the prolonged QT interval. The inherited forms are caused by mutation of genes encoding cardiac ion channel proteins. The two major forms are ROMANO-WARD SYNDROME and JERVELL-LANGE NIELSEN SYNDROME.
Last Evaluated: Jul 10, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 20:33412656
Long QT syndrome (LQTS) is a cardiac electrophysiologic disorder, characterized by QT prolongation and T-wave abnormalities on the ECG that are associated with tachyarrhythmias, typically the ventricular tachycardia torsade de pointes (TdP). TdP is usually self-terminating, thus causing a syncopal event, the most common symptom in individuals with LQTS. Such cardiac events typically occur during exercise and emotional stress, less frequently during sleep, and usually without warning. In some instances, TdP degenerates to ventricular fibrillation and causes aborted cardiac arrest (if the individual is defibrillated) or sudden death. Approximately 50% of untreated individuals with a pathogenic variant in one of the genes associated with LQTS have symptoms, usually one to a few syncopal events. While cardiac events may occur from infancy through middle age, they are most common from the preteen years through the 20s. Some types of LQTS are associated with a phenotype extending beyond cardiac arrhythmia. In addition to the prolonged QT interval, associations include muscle weakness and facial dysmorphism in Andersen-Tawil syndrome (LQTS type 7), hand/foot, facial, and neurodevelopmental features in Timothy syndrome (LQTS type 8), and profound sensorineural hearing loss in Jervell and Lange-Nielson syndrome.
Last Evaluated: Jul 10, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 20:33412656
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Below are uncommon mutations (frequency between 1% and 5%) found in ClinVar. The data presented has no guarantees of reporting accuracy. Heterozygous variants are repoted as yellow and homozygous variants as red. A red or yellow variant does not necessarily mean one has or carries a condition or disease. This is for research and educational purposes only.
Gene:
KCNJ10
Variant:
c.53G>A
(p.Arg18Gln)
rsID: rs115466046
Ref Allele: C
Alt Allele: T
Freq: 1.0058%uncommon
CADD: 18.47
ClinVar Submissions (8)
Last Evaluated: Mar 08, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:160042480
Syndrome with characteristics of seizures, sensorineural deafness, ataxia, intellectual deficit, and electrolyte imbalance. It has been described in five patients from four families. The disease is caused by homozygous or compound heterozygous mutations in the KCNJ10 gene, encoding a potassium channel expressed in the brain, spinal cord, inner ear and kidneys. Transmission is autosomal recessive.
Last Evaluated: Mar 08, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:160042480
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Mar 08, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:160042480
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 08, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:160042480
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
LRIT3
Variant:
c.-14C>G
rsID: rs77613966
Ref Allele: C
Alt Allele: G
Freq: 1.0066%uncommon
CADD: 0.714
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 4:109848188
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
KCNA5
Variant:
c.751G>A
(p.Ala251Thr)
rsID: rs12720442
Ref Allele: G
Alt Allele: A
Freq: 1.0106%uncommon
CADD: 21.1
ClinVar Submissions (4)
Atrial fibrillation (AF) is the most common sustained cardiac rhythm disturbance, affecting more than 2 million Americans, with an overall prevalence of 0.89%. The prevalence increases rapidly with age, to 2.3% between the ages of 40 and 60 years, and to 5.9% over the age of 65. The most dreaded complication is thromboembolic stroke (Brugada et al., 1997). For a discussion of genetic heterogeneity of atrial fibrillation, see 608583.
Last Evaluated: Jul 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:5044898
Familial atrial fibrillation is an inherited abnormality of the heart's normal rhythm. Atrial fibrillation is characterized by episodes of uncoordinated electrical activity (fibrillation) in the heart's upper chambers (the atria), which cause a fast and irregular heartbeat. If untreated, this abnormal heart rhythm (arrhythmia) can lead to dizziness, chest pain, a sensation of fluttering or pounding in the chest (palpitations), shortness of breath, or fainting (syncope). Atrial fibrillation also increases the risk of stroke and sudden death. Complications of atrial fibrillation can occur at any age, although some people with this heart condition never experience any health problems associated with the disorder.
Last Evaluated: Jul 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:5044898
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:5044898
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
OPA1
Variant:
c.*2408A>G
rsID: rs73069788
Ref Allele: A
Alt Allele: G
Freq: 1.017%uncommon
CADD: 4.448
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:193697008
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
LRIT3
Variant:
c.*550G>A
rsID: rs76150278
Ref Allele: G
Alt Allele: A
Freq: 1.0297%uncommon
CADD: 3.922
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 4:109871339
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
LRIT3
Variant:
c.331C>G
(p.Arg111Gly)
rsID: rs79039619
Ref Allele: C
Alt Allele: G
Freq: 1.0313%uncommon
CADD: 23.5
ClinVar Submissions (2)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:109851718
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:109851718
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
LRIT3
Variant:
c.565C>T
(p.Leu189Phe)
rsID: rs75301950
Ref Allele: C
Alt Allele: T
Freq: 1.0321%uncommon
CADD: 0.057
ClinVar Submissions (2)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:109851952
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:109851952
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
LRIT3
Variant:
c.1509G>A
(p.Thr503=)
rsID: rs76587489
Ref Allele: G
Alt Allele: A
Freq: 1.0345%uncommon
CADD: 2.814
ClinVar Submissions (2)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:109870258
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:109870258
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
LRIT3
Variant:
c.*103A>G
rsID: rs76050257
Ref Allele: A
Alt Allele: G
Freq: 1.0441%uncommon
CADD: 4.078
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 4:109870892
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
OXCT1
Variant:
c.*1434G>C
rsID: rs77675837
Ref Allele: C
Alt Allele: G
Freq: 1.0703%uncommon
CADD: 0.256
ClinVar Submissions (1)
Ketone bodies are major vectors of energy transfer from the liver to extrahepatic tissues and are the main source of lipid-derived energy for the brain. Mitchell et al. (1995) reviewed medical aspects of ketone body metabolism, including the differential diagnosis of abnormalities. As the first step of ketone body utilization, succinyl-CoA:3-oxoacid CoA transferase (SCOT, or OXCT1; EC 2.8.3.5) catalyzes the reversible transfer of CoA from succinyl-CoA to acetoacetate.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:41730295
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Homo
Gene:
CHRNE
Variant:
c.966C>T
(p.Cys322=)
rsID: rs56377005
Ref Allele: G
Alt Allele: A
Freq: 1.0751%uncommon
CADD: 16.54
ClinVar Submissions (4)
Last Evaluated: Aug 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:4899534
Congenital myasthenic syndromes (designated as CMS throughout this entry) are characterized by fatigable weakness of skeletal muscle (e.g., ocular, bulbar, limb muscles) with onset at or shortly after birth or in early childhood; rarely, symptoms may not manifest until later in childhood. Cardiac and smooth muscle are usually not involved. Severity and course of disease are highly variable, ranging from minor symptoms to progressive disabling weakness. In some subtypes of CMS, myasthenic symptoms may be mild, but sudden severe exacerbations of weakness or even sudden episodes of respiratory insufficiency may be precipitated by fever, infections, or excitement. Major findings of the neonatal-onset subtype include: respiratory insufficiency with sudden apnea and cyanosis; feeding difficulties; poor suck and cry; choking spells; eyelid ptosis; and facial, bulbar, and generalized weakness. Arthrogryposis multiplex congenita may also be present. Stridor in infancy may be an important clue to CMS. Later childhood-onset subtypes show abnormal muscle fatigability with difficulty in activities such as running or climbing stairs; motor milestones may be delayed; fluctuating eyelid ptosis and fixed or fluctuating extraocular muscle weakness are common presentations.
Last Evaluated: Aug 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:4899534
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:4899534
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
GLI2
Variant:
c.4558G>A
(p.Asp1520Asn)
rsID: rs114814747
Ref Allele: G
Alt Allele: A
Freq: 1.0759%uncommon
CADD: 32
ClinVar Submissions (6)
Last Evaluated: Oct 29, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:120990472
OMIM Allelic Variant: 165230.0007
Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having "microform" HPE.
Last Evaluated: Oct 29, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:120990472
OMIM Allelic Variant: 165230.0007
Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having "microform" HPE.
Last Evaluated: Oct 29, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:120990472
OMIM Allelic Variant: 165230.0007
Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having "microform" HPE.
Last Evaluated: Oct 29, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:120990472
OMIM Allelic Variant: 165230.0007
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 29, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:120990472
OMIM Allelic Variant: 165230.0007
This individual has one copy of the genetic mutation, and because the condition(s) are autosomal dominant, they may manifest the condition rather than just being a carrier. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
STXBP1
Variant:
c.663+17C>T
rsID: rs140247913
Ref Allele: C
Alt Allele: T
Freq: 1.0839%uncommon
CADD: 0.489
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 26, 2012
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:127665348
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
FANCA
Variant:
c.*679T>G
rsID: rs17233833
Ref Allele: A
Alt Allele: C
Freq: 1.0934%uncommon
CADD: 1.01
ClinVar Submissions (1)
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract – are more common in individuals with FA.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 16:89737922
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
IFT172
Variant:
c.571-15C>G
rsID: rs75809198
Ref Allele: G
Alt Allele: C
Freq: 1.1078%uncommon
CADD: 13.29
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 05, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:27481275
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
IGHMBP2
Variant:
c.2782G>A
(p.Glu928Lys)
rsID: rs2275996
Ref Allele: G
Alt Allele: A
Freq: 1.1086%uncommon
CADD: 34
ClinVar Submissions (4)
Charcot-Marie-Tooth disease type 2S is a relatively pure form of autosomal recessive axonal neuropathy characterized by onset in the first decade of slowly progressive distal muscle weakness and atrophy affecting the lower and upper limbs. Patients have decreased reflexes and variable distal sensory impairment (summary by Cottenie et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).
Last Evaluated: Sep 20, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:68938352
Spinal muscular atrophy (SMA) is characterized by muscle weakness and atrophy resulting from progressive degeneration and loss of the anterior horn cells in the spinal cord (i.e., lower motor neurons) and the brain stem nuclei. The onset of weakness ranges from before birth to adolescence or young adulthood. The weakness is symmetric, proximal > distal, and progressive. Before the genetic basis of SMA was understood, it was classified into clinical subtypes; however, it is now apparent that the phenotype of SMN1-associated SMA spans a continuum without clear delineation of subtypes. Poor weight gain with growth failure, restrictive lung disease, scoliosis, joint contractures, and sleep difficulties are common complications.
Last Evaluated: Sep 20, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:68938352
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an inherited condition that causes muscle weakness and respiratory failure typically beginning in infancy. Early features of this condition are difficult and noisy breathing, especially when inhaling; a weak cry; problems feeding; and recurrent episodes of pneumonia. Typically between the ages of 6 weeks and 6 months, infants with this condition will experience a sudden inability to breathe due to paralysis of the muscle that separates the abdomen from the chest cavity (the diaphragm). Normally, the diaphragm contracts and moves downward during inhalation to allow the lungs to expand. With diaphragm paralysis, affected individuals require life-long support with a machine to help them breathe (mechanical ventilation). Rarely, children with SMARD1 develop signs or symptoms of the disorder later in childhood.Soon after respiratory failure occurs, individuals with SMARD1 develop muscle weakness in their distal muscles. These are the muscles farther from the center of the body, such as muscles in the hands and feet. The weakness soon spreads to all muscles; however, within 2 years, the muscle weakness typically stops getting worse. Some individuals may retain a low level of muscle function, while others lose all ability to move their muscles. Muscle weakness severely impairs motor development, such as sitting, standing, and walking. Some affected children develop an abnormal side-to-side and back-to-front curvature of the spine (scoliosis and kyphosis, often called kyphoscoliosis when they occur together). After approximately the first year of life, individuals with SMARD1 may lose their deep tendon reflexes, such as the reflex being tested when a doctor taps the knee with a hammer.Other features of SMARD1 can include reduced pain sensitivity, excessive sweating (hyperhidrosis), loss of bladder and bowel control, and an irregular heartbeat (arrhythmia).
Last Evaluated: Sep 20, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:68938352
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Sep 20, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:68938352
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 20, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:68938352
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
FANCA
Variant:
c.1627-32T>C
rsID: rs17226337
Ref Allele: A
Alt Allele: G
Freq: 1.1348%uncommon
CADD: 4.245
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:89779989
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
MYLK
Variant:
c.2533C>T
(p.Arg845Cys)
rsID: rs3732485
Ref Allele: G
Alt Allele: A
Freq: 1.1364%uncommon
CADD: 12.16
ClinVar Submissions (8)
Familial thoracic aortic aneurysm and dissection (familial TAAD) involves problems with the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. Familial TAAD affects the upper part of the aorta, near the heart. This part of the aorta is called the thoracic aorta because it is located in the chest (thorax). Other vessels that carry blood from the heart to the rest of the body (arteries) can also be affected.In familial TAAD, the aorta can become weakened and stretched (aortic dilatation), which can lead to a bulge in the blood vessel wall (an aneurysm). Aortic dilatation may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection), allowing blood to flow abnormally between the layers. These aortic abnormalities are potentially life-threatening because they can decrease blood flow to other parts of the body such as the brain or other vital organs, or cause the aorta to break open (rupture).The occurrence and timing of these aortic abnormalities vary, even within the same affected family. They can begin in childhood or not occur until late in life. Aortic dilatation is generally the first feature of familial TAAD to develop, although in some affected individuals dissection occurs with little or no aortic dilatation.Aortic aneurysms usually have no symptoms. However, depending on the size, growth rate, and location of these abnormalities, they can cause pain in the jaw, neck, chest, or back; swelling in the arms, neck, or head; difficult or painful swallowing; hoarseness; shortness of breath; wheezing; a chronic cough; or coughing up blood. Aortic dissections usually cause severe, sudden chest or back pain, and may also result in unusually pale skin (pallor), a very faint pulse, numbness or tingling (paresthesias) in one or more limbs, or paralysis.Familial TAAD may not be associated with other signs and symptoms. However, some individuals in affected families show mild features of related conditions called Marfan syndrome or Loeys-Dietz syndrome. These features include tall stature, stretch marks on the skin, an unusually large range of joint movement (joint hypermobility), and either a sunken or protruding chest. Occasionally, people with familial TAAD develop aneurysms in the brain or in the section of the aorta located in the abdomen (abdominal aorta). Some people with familial TAAD have heart abnormalities that are present from birth (congenital). Affected individuals may also have a soft out-pouching in the lower abdomen (inguinal hernia), an abnormal curvature of the spine (scoliosis), or a purplish skin discoloration (livedo reticularis) caused by abnormalities in the tiny blood vessels of the skin (dermal capillaries). However, these conditions are also common in the general population. Depending on the genetic cause of familial TAAD in particular families, they may have an increased risk of developing blockages in smaller arteries, which can lead to heart attack and stroke.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123700935
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123700935
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123700935
Familial thoracic aortic aneurysm and dissection (familial TAAD) involves problems with the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. Familial TAAD affects the upper part of the aorta, near the heart. This part of the aorta is called the thoracic aorta because it is located in the chest (thorax). Other vessels that carry blood from the heart to the rest of the body (arteries) can also be affected.In familial TAAD, the aorta can become weakened and stretched (aortic dilatation), which can lead to a bulge in the blood vessel wall (an aneurysm). Aortic dilatation may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection), allowing blood to flow abnormally between the layers. These aortic abnormalities are potentially life-threatening because they can decrease blood flow to other parts of the body such as the brain or other vital organs, or cause the aorta to break open (rupture).The occurrence and timing of these aortic abnormalities vary, even within the same affected family. They can begin in childhood or not occur until late in life. Aortic dilatation is generally the first feature of familial TAAD to develop, although in some affected individuals dissection occurs with little or no aortic dilatation.Aortic aneurysms usually have no symptoms. However, depending on the size, growth rate, and location of these abnormalities, they can cause pain in the jaw, neck, chest, or back; swelling in the arms, neck, or head; difficult or painful swallowing; hoarseness; shortness of breath; wheezing; a chronic cough; or coughing up blood. Aortic dissections usually cause severe, sudden chest or back pain, and may also result in unusually pale skin (pallor), a very faint pulse, numbness or tingling (paresthesias) in one or more limbs, or paralysis.Familial TAAD may not be associated with other signs and symptoms. However, some individuals in affected families show mild features of related conditions called Marfan syndrome or Loeys-Dietz syndrome. These features include tall stature, stretch marks on the skin, an unusually large range of joint movement (joint hypermobility), and either a sunken or protruding chest. Occasionally, people with familial TAAD develop aneurysms in the brain or in the section of the aorta located in the abdomen (abdominal aorta). Some people with familial TAAD have heart abnormalities that are present from birth (congenital). Affected individuals may also have a soft out-pouching in the lower abdomen (inguinal hernia), an abnormal curvature of the spine (scoliosis), or a purplish skin discoloration (livedo reticularis) caused by abnormalities in the tiny blood vessels of the skin (dermal capillaries). However, these conditions are also common in the general population. Depending on the genetic cause of familial TAAD in particular families, they may have an increased risk of developing blockages in smaller arteries, which can lead to heart attack and stroke.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123700935
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123700935
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123700935
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
SLC5A1
Variant:
c.6C>T
(p.Asp2=)
rsID: rs33973317
Ref Allele: C
Alt Allele: T
Freq: 1.1468%uncommon
CADD: 12.2
ClinVar Submissions (1)
Glucose/galactose malabsorption (GGM) is a rare autosomal recessive disorder caused by a defect in glucose and galactose transport across the intestinal brush border. Patients with GGM present with neonatal onset of severe life-threatening watery diarrhea and dehydration. If diagnosed and treated properly, patients can fully recover and show normal growth and development (summary by Xin and Wang, 2011).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 22:32043287
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
PIGO
Variant:
c.1404A>C
(p.Ala468=)
rsID: rs35287398
Ref Allele: T
Alt Allele: G
Freq: 1.1516%uncommon
CADD: 17.14
ClinVar Submissions (4)
Hyperphosphatasia with mental retardation syndrome-2 is an autosomal recessive disorder characterized by moderately to severely delayed psychomotor development, facial dysmorphism, brachytelephalangy, and increased serum alkaline phosphatase (hyperphosphatasia). Some patients may have additional features, such as cardiac septal defects or seizures (summary by Krawitz et al., 2012). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of hyperphosphatasia with mental retardation syndrome, see HPMRS1 (239300). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:35092483
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:35092483
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
DYNC2H1
Variant:
c.2860G>A
(p.Glu954Lys)
rsID: rs61898615
Ref Allele: G
Alt Allele: A
Freq: 1.1579%uncommon
CADD: 22.7
ClinVar Submissions (4)
Asphyxiating thoracic dystrophy, also known as Jeune syndrome, is an inherited disorder of bone growth characterized by a narrow chest, short ribs, shortened bones in the arms and legs, short stature, and extra fingers and toes (polydactyly). Additional skeletal abnormalities can include unusually shaped collarbones (clavicles) and pelvic bones, and and cone-shaped ends of the long bones in the arms and legs. Many infants with this condition are born with an extremely narrow, bell-shaped chest that can restrict the growth and expansion of the lungs. Life-threatening problems with breathing result, and people with asphyxiating thoracic dystrophy may live only into infancy or early childhood. However, in people who survive beyond the first few years, the narrow chest and related breathing problems can improve with age.Some people with asphyxiating thoracic dystrophy are born with less severe skeletal abnormalities and have only mild breathing difficulties, such as rapid breathing or shortness of breath. These individuals may live into adolescence or adulthood. After infancy, people with this condition may develop life-threatening kidney (renal) abnormalities that cause the kidneys to malfunction or fail. Heart defects and a narrowing of the airway (subglottic stenosis) are also possible. Other, less common features of asphyxiating thoracic dystrophy include liver disease, fluid-filled sacs (cysts) in the pancreas, dental abnormalities, and an eye disease called retinal dystrophy that can lead to vision loss.
Last Evaluated: Nov 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:103148531
A rare congenital lethal syndrome characterized by the presence of extra fingers and toes and short ribs, the latter resulting in inability of the lungs to expand. The newborn dies shortly after birth.
Last Evaluated: Nov 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:103148531
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Nov 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:103148531
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:103148531
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
TOR1A
Variant:
c.749-11C>A
rsID: rs72755217
Ref Allele: G
Alt Allele: T
Freq: 1.1587%uncommon
CADD: 4.573
ClinVar Submissions (2)
DYT1 early-onset isolated dystonia typically presents in childhood or adolescence and only on occasion in adulthood. Dystonic muscle contractions causing posturing or irregular tremor of a leg or arm are the most common presenting findings. Dystonia is usually first apparent with specific actions such as writing or walking. Over time, the contractions frequently (but not invariably) become evident with less specific actions and spread to other body regions. No other neurologic abnormalities are present. Disease severity varies considerably even within the same family. Isolated writer's cramp may be the only sign.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:129814233
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:129814233
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
THAP1
Variant:
c.*135T>A
rsID: rs181850921
Ref Allele: A
Alt Allele: T
Freq: 1.1595%uncommon
CADD: 8.664
ClinVar Submissions (1)
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 8:42837827
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
IFT122
Variant:
c.1866G>T
(p.Ser622=)
rsID: rs150174636
Ref Allele: G
Alt Allele: T
Freq: 1.1683%uncommon
CADD: 3.573
ClinVar Submissions (2)
Cranioectodermal dysplasia (CED), a ciliopathy also known as Sensenbrenner syndrome, is a multisystem disorder with skeletal involvement (narrow thorax, shortened proximal limbs, and brachydactyly), ectodermal features (widely-spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth retardation, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus/epicanthus, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage renal disease (ESRD) in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy, other manifestations of ciliopathies, are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur.
Last Evaluated: Mar 22, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:129483544
Cranioectodermal dysplasia (CED), a ciliopathy also known as Sensenbrenner syndrome, is a multisystem disorder with skeletal involvement (narrow thorax, shortened proximal limbs, and brachydactyly), ectodermal features (widely-spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth retardation, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus/epicanthus, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage renal disease (ESRD) in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy, other manifestations of ciliopathies, are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur.
Last Evaluated: Mar 22, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:129483544
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
BMP1
Variant:
c.*350C>T
rsID: rs77383472
Ref Allele: C
Alt Allele: T
Freq: 1.1723%uncommon
CADD: 0.994
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:22212078
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
BMP1
Variant:
c.*108A>C
rsID: rs556361110
Ref Allele: A
Alt Allele: C
Freq: 1.1994%uncommon
CADD: 4.353
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:22211836
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
PMM2
Variant:
c.324G>A
(p.Ala108=)
rsID: rs62031146
Ref Allele: G
Alt Allele: A
Freq: 1.1994%uncommon
CADD: 0.968
ClinVar Submissions (7)
PMM2-CDG (CDG-Ia) (previously known as congenital disorder of glycosylation type 1a), the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides, is divided into three types: infantile multisystem, late-infantile and childhood ataxia-intellectual disability, and adult stable disability. The three types notwithstanding, clinical presentation and course are highly variable, ranging from infants who die in the first year of life to mildly involved adults. Clinical presentations tend to be similar in sibs. In the infantile multisystem type, infants show axial hypotonia, hyporeflexia, esotropia, and developmental delay. Feeding problems, vomiting, failure to thrive, and impaired growth are frequently seen. Subcutaneous fat may be excessive over the buttocks and suprapubic region. Two distinct clinical presentations are observed: (1) a non-fatal neurologic form with strabismus, psychomotor retardation, and cerebellar hypoplasia in infancy followed by neuropathy and retinitis pigmentosa in the first or second decade and (2) a neurologic-multivisceral form with approximately 20% mortality in the first year of life. The late-infantile and childhood ataxia-intellectual disability type, with onset between age three and ten years, is characterized by hypotonia, ataxia, severely delayed language and motor development, inability to walk, and IQ of 40 to 70; other findings include seizures, stroke-like episodes or transient unilateral loss of function, retinitis pigmentosa, joint contractures, and skeletal deformities. In the adult stable disability type, intellectual ability is stable; peripheral neuropathy is variable, thoracic and spinal deformities progress, and premature aging is observed; females lack secondary sexual development and males may exhibit decreased testicular volume. Hyperglycemia-induced growth hormone release, hyperprolactinemia, insulin resistance, and coagulopathy may occur. An increased risk for deep venous thrombosis is present.
Last Evaluated: May 25, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 16:8806384
A genetically heterogeneous group of heritable disorders resulting from defects in protein N-glycosylation.
Last Evaluated: May 25, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 16:8806384
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 25, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 16:8806384
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
NOTCH1
Variant:
c.2691C>T
(p.Ala897=)
rsID: rs11574895
Ref Allele: G
Alt Allele: A
Freq: 1.2121%uncommon
CADD: 0.019
ClinVar Submissions (4)
Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies.
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:136510702
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:136510702
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:136510702
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
RAPSN
Variant:
c.614G>A
(p.Arg205Gln)
rsID: rs34625105
Ref Allele: C
Alt Allele: T
Freq: 1.2121%uncommon
CADD: 23.5
ClinVar Submissions (4)
Last Evaluated: Jul 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:47442732
Congenital myasthenic syndromes (designated as CMS throughout this entry) are characterized by fatigable weakness of skeletal muscle (e.g., ocular, bulbar, limb muscles) with onset at or shortly after birth or in early childhood; rarely, symptoms may not manifest until later in childhood. Cardiac and smooth muscle are usually not involved. Severity and course of disease are highly variable, ranging from minor symptoms to progressive disabling weakness. In some subtypes of CMS, myasthenic symptoms may be mild, but sudden severe exacerbations of weakness or even sudden episodes of respiratory insufficiency may be precipitated by fever, infections, or excitement. Major findings of the neonatal-onset subtype include: respiratory insufficiency with sudden apnea and cyanosis; feeding difficulties; poor suck and cry; choking spells; eyelid ptosis; and facial, bulbar, and generalized weakness. Arthrogryposis multiplex congenita may also be present. Stridor in infancy may be an important clue to CMS. Later childhood-onset subtypes show abnormal muscle fatigability with difficulty in activities such as running or climbing stairs; motor milestones may be delayed; fluctuating eyelid ptosis and fixed or fluctuating extraocular muscle weakness are common presentations.
Last Evaluated: Jul 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:47442732
The fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous constellation of features including fetal akinesia, intrauterine growth retardation, arthrogryposis, and developmental anomalies, including lung hypoplasia, cleft palate, and cryptorchidism (Vogt et al., 2009). It shows phenotypic overlap with the lethal form of multiple pterygium syndrome (see 253290).
Last Evaluated: Jul 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:47442732
The fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous constellation of features including fetal akinesia, intrauterine growth retardation, arthrogryposis, and developmental anomalies, including lung hypoplasia, cleft palate, and cryptorchidism (Vogt et al., 2009). It shows phenotypic overlap with the lethal form of multiple pterygium syndrome (see 253290).
Last Evaluated: Jul 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:47442732
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:47442732
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
NOTCH1
Variant:
c.2664C>T
(p.His888=)
rsID: rs61751548
Ref Allele: G
Alt Allele: A
Freq: 1.236%uncommon
CADD: 0.968
ClinVar Submissions (4)
Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies.
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:136510729
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:136510729
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:136510729
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
IFITM5
Variant:
c.-27A>G
rsID: rs113160876
Ref Allele: T
Alt Allele: C
Freq: 1.279%uncommon
CADD: 9.101
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 10, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:299517
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Homo
Gene:
CATSPER1
Variant:
c.730G>A
(p.Gly244Arg)
rsID: rs79062509
Ref Allele: C
Alt Allele: T
Freq: 1.2838%uncommon
CADD: 8.309
ClinVar Submissions (1)
The inability of the male to effect FERTILIZATION of an OVUM after a specified period of unprotected intercourse. Male sterility is permanent infertility.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:66025650
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
USH2A
Variant:
c.688G>A
(p.Val230Met)
rsID: rs45500891
Ref Allele: C
Alt Allele: T
Freq: 1.3045%uncommon
CADD: 10.87
ClinVar Submissions (5)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:216365049
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:216365049
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Low clinical importance, Uncertain benign — This rare variant may be associated with Usher Syndrome II, but the literature seems to have concluded that it is a non-pathogenic polymorphism (including authors who earlier reported it as pathogenic).
Benign
Hetero
Gene:
LPIN1
Variant:
c.1480G>A
(p.Val494Met)
rsID: rs33997857
Ref Allele: G
Alt Allele: A
Freq: 1.3228%uncommon
CADD: 25.4
ClinVar Submissions (3)
Last Evaluated: Nov 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:11787112
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:11787112
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
SCN4B
Variant:
c.*1071T>C
rsID: rs117263855
Ref Allele: A
Alt Allele: G
Freq: 1.3363%uncommon
CADD: 5.467
ClinVar Submissions (1)
A condition that is characterized by episodes of fainting (SYNCOPE) and varying degree of ventricular arrhythmia as indicated by the prolonged QT interval. The inherited forms are caused by mutation of genes encoding cardiac ion channel proteins. The two major forms are ROMANO-WARD SYNDROME and JERVELL-LANGE NIELSEN SYNDROME.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:118135956
Long QT syndrome (LQTS) is a cardiac electrophysiologic disorder, characterized by QT prolongation and T-wave abnormalities on the ECG that are associated with tachyarrhythmias, typically the ventricular tachycardia torsade de pointes (TdP). TdP is usually self-terminating, thus causing a syncopal event, the most common symptom in individuals with LQTS. Such cardiac events typically occur during exercise and emotional stress, less frequently during sleep, and usually without warning. In some instances, TdP degenerates to ventricular fibrillation and causes aborted cardiac arrest (if the individual is defibrillated) or sudden death. Approximately 50% of untreated individuals with a pathogenic variant in one of the genes associated with LQTS have symptoms, usually one to a few syncopal events. While cardiac events may occur from infancy through middle age, they are most common from the preteen years through the 20s. Some types of LQTS are associated with a phenotype extending beyond cardiac arrhythmia. In addition to the prolonged QT interval, associations include muscle weakness and facial dysmorphism in Andersen-Tawil syndrome (LQTS type 7), hand/foot, facial, and neurodevelopmental features in Timothy syndrome (LQTS type 8), and profound sensorineural hearing loss in Jervell and Lange-Nielson syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:118135956
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
FZD4
Variant:
c.*2660C>T
rsID: rs11234890
Ref Allele: G
Alt Allele: A
Freq: 1.3443%uncommon
CADD: 14.7
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:86948482
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
STX16
Variant:
c.*1899C>T
rsID: rs138678203
Ref Allele: C
Alt Allele: T
Freq: 1.3507%uncommon
CADD: 3.244
ClinVar Submissions (1)
Autosomal dominant pseudohypoaldosteronism type I is characterized by salt wasting resulting from renal unresponsiveness to mineralocorticoids. Patients may present with neonatal renal salt wasting with hyperkalaemic acidosis despite high aldosterone levels. These patients improve with age and usually become asymptomatic without treatment. Some adult patients with the disorder may have elevated aldosterone levels, but no history of clinical disease. This observation suggests that only those infants whose salt homeostasis is stressed by intercurrent illness and volume depletion develop clinically recognized PHA I (summary by Geller et al., 1998). Autosomal recessive pseudohypoaldosteronism type I (PHA1B; 264350), caused by mutation in any one of 3 genes encoding the epithelial sodium channel (ENaC), is a similar but more severe systemic disorder with persistence into adulthood.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 20:58678190
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
PKD2
Variant:
c.-82G>C
rsID: rs529779778
Ref Allele: G
Alt Allele: C
Freq: 1.3682%uncommon
CADD: 12.1
ClinVar Submissions (1)
Autosomal dominant polycystic kidney disease (ADPKD) is generally a late-onset multisystem disorder characterized by bilateral renal cysts, liver cysts, and an increased risk of intracranial aneurysms. Other manifestations include: cysts in the pancreas, seminal vesicles, and arachnoid membrane; dilatation of the aortic root and dissection of the thoracic aorta; mitral valve prolapse; and abdominal wall hernias. Renal manifestations include hypertension, renal pain, and renal insufficiency. Approximately 50% of individuals with ADPKD have end-stage renal disease (ESRD) by age 60 years. The prevalence of liver cysts increases with age and occasionally results in clinically significant severe polycystic liver disease (PLD). Overall the prevalence of intracranial aneurysms is fivefold higher than in the general population and further increased in those with a positive family history of aneurysms or subarachnoid hemorrhage. There is substantial variability in the severity of renal disease and other extrarenal manifestations even within the same family.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 4:88007652
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
PEX2
Variant:
c.*1194A>G
rsID: rs4311633
Ref Allele: T
Alt Allele: C
Freq: 1.4279%uncommon
CADD: 2.031
ClinVar Submissions (1)
Zellweger spectrum disorder (ZSD) is a phenotypic continuum ranging from severe to mild. While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term ZSD is now used to refer to all individuals with a PEX gene defect regardless of phenotype. Individuals with ZSD usually come to clinical attention in the newborn period or later in childhood. Affected newborns are hypotonic and feed poorly. They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling [chondrodysplasia punctata] of the patella[e] and other long bones), and liver disease which can be severe. Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress. Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss); neurologic involvement (ataxia, polyneuropathy, and leukodystrophy); liver dysfunction; adrenal insufficiency; and renal oxalate stones. While hypotonia and developmental delays are typical, intellect can be normal. Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 8:76982067
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
TGM5
Variant:
c.1106-7C>T
rsID: rs113249183
Ref Allele: G
Alt Allele: A
Freq: 1.4638%uncommon
CADD: 9.435
ClinVar Submissions (1)
Peeling skin syndrome is a rare genodermatosis with variable age of onset from birth to adulthood. Clinically, it is characterized by a pruritic or nonpruritic spontaneous superficial peeling of the skin, which sometimes is accompanied by erythema or vesiculation. The skin involvement is usually general, but in some patients the scalp, face, palms, and soles may be unaffected. Seasonal changes have been reported. The histologic picture is characterized by separation of the epidermis between the statum corneum and the stratum granulosum (summary by Hacham-Zadeh and Holubar, 1985). Generalized PSS has been subclassified into a noninflammatory type, designated type A, and an inflammatory type, designated type B (Traupe, 1989; Judge et al., 2004). Type B, in which generalized peeling skin is associated with pruritus and atopy, is characterized by lifelong patchy peeling of the entire skin with onset at birth or shortly thereafter. Several patients have been reported with high IgE levels (summary by Oji et al., 2010). Type A, a continuous nonerythematous exfoliation, is usually congenital or appears during childhood (summary by Mallet et al., 2013). Genetic Heterogeneity of Peeling Skin Syndrome Peeling skin syndrome-2 (PSS2; 609796), an acral form of the disorder that mainly involves palmar and plantar skin, is caused by mutation in the TGM5 gene (603805) on chromosome 15q15. Peeling skin syndrome-3 (PSS3; 616265) is caused by mutation in the CHST8 gene (610190) on chromosome 19q13. Peeling skin syndrome-4 (PSS4; 607936) is caused by mutation in the CSTA gene (184600) on chromosome 3q21. Peeling skin syndrome-5 (PSS5; 617115) is caused by mutation in the SERPINB8 gene (601697) on chromosome 18q22. PSS6 (618084) is caused by mutation in the FLG2 gene (616284) on chromosome 1q21.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 15:43239063
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
DNAH11
Variant:
c.9102+8G>A
rsID: rs72657374
Ref Allele: G
Alt Allele: A
Freq: 1.4725%uncommon
CADD: 2.511
ClinVar Submissions (4)
Primary ciliary dyskinesia (PCD) is associated with situs abnormalities, abnormal sperm motility, and abnormal ciliary structure and function that result in retention of mucus and bacteria in the respiratory tract leading to chronic otosinopulmonary disease. More than 75% of full-term neonates with PCD have "neonatal respiratory distress" requiring supplemental oxygen for days to weeks. Chronic airway infection, apparent in early childhood, results in bronchiectasis that is almost uniformly present in adulthood. Nasal congestion and sinus infections, apparent in early childhood, persist through adulthood. Chronic/recurrent ear infection, apparent in most young children, can be associated with transient or later irreversible hearing loss. Situs inversus totalis (mirror-image reversal of all visceral organs with no apparent physiologic consequences) is present in 40%-50% of individuals with PCD; heterotaxy (discordance of right and left patterns of ordinarily asymmetric structures that can be associated with significant malformations) is present in approximately 12%. Virtually all males with PCD are infertile as a result of abnormal sperm motility.
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:21765597
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:21765597
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
BARD1
Variant:
c.158+3299C>T
rsID: rs142776370
Ref Allele: G
Alt Allele: A
Freq: 1.4797%uncommon
CADD: 12.96
ClinVar Submissions (1)
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Dec 01, 2015
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:214806113
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
NEK1
Variant:
c.2680+12T>A
rsID: rs77658514
Ref Allele: A
Alt Allele: T
Freq: 1.4868%uncommon
CADD: 4.015
ClinVar Submissions (2)
A rare congenital lethal syndrome characterized by the presence of extra fingers and toes and short ribs, the latter resulting in inability of the lungs to expand. The newborn dies shortly after birth.
Last Evaluated: Jan 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:169438071
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:169438071
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
CUL4B
Variant:
c.1378+15G>A
rsID: rs143921252
Ref Allele: C
Alt Allele: T
Freq: 1.5338%uncommon
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 13, 2015
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: X:120542951
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Homo
Gene:
ABCC6
Variant:
c.3190C>T
(p.Arg1064Trp)
rsID: rs41278174
Ref Allele: G
Alt Allele: A
Freq: 1.5506%uncommon
CADD: 26
ClinVar Submissions (1)
Pseudoxanthoma elasticum (PXE) is a systemic disorder that affects the elastic tissue of the skin, the eye, and the cardiovascular and gastrointestinal systems. Individuals most commonly present with papules in the skin and/or with angioid streaks of the retina found on routine eye examination or associated with retinal hemorrhage. Rarely, individuals may present with vascular signs and symptoms, such as gastrointestinal bleeding, angina, or intermittent claudication. The most frequent cause of morbidity and disability in PXE is reduced vision from macular hemorrhage and disciform scarring of the macula. Most affected individuals live a normal life span.
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:16165739
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
DRC1
Variant:
c.1359C>T
(p.Ser453=)
rsID: rs77226260
Ref Allele: C
Alt Allele: T
Freq: 1.5561%uncommon
CADD: 0.007
ClinVar Submissions (1)
Primary ciliary dyskinesia (PCD) is associated with situs abnormalities, abnormal sperm motility, and abnormal ciliary structure and function that result in retention of mucus and bacteria in the respiratory tract leading to chronic otosinopulmonary disease. More than 75% of full-term neonates with PCD have "neonatal respiratory distress" requiring supplemental oxygen for days to weeks. Chronic airway infection, apparent in early childhood, results in bronchiectasis that is almost uniformly present in adulthood. Nasal congestion and sinus infections, apparent in early childhood, persist through adulthood. Chronic/recurrent ear infection, apparent in most young children, can be associated with transient or later irreversible hearing loss. Situs inversus totalis (mirror-image reversal of all visceral organs with no apparent physiologic consequences) is present in 40%-50% of individuals with PCD; heterotaxy (discordance of right and left patterns of ordinarily asymmetric structures that can be associated with significant malformations) is present in approximately 12%. Virtually all males with PCD are infertile as a result of abnormal sperm motility.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:26444911
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
LMNB1
Variant:
c.1502C>T
(p.Ala501Val)
rsID: rs36105360
Ref Allele: C
Alt Allele: T
Freq: 1.584%uncommon
CADD: 22.4
ClinVar Submissions (2)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:126825998
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:126825998
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
SPEF2
Variant:
c.2840-13G>A
rsID: rs115898419
Ref Allele: G
Alt Allele: A
Freq: 1.5912%uncommon
CADD: 15.16
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 29, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:35712799
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
TRIP11
Variant:
c.5781G>A
(p.Ser1927=)
rsID: rs3742719
Ref Allele: C
Alt Allele: T
Freq: 1.6302%uncommon
CADD: 1.05
ClinVar Submissions (3)
A rare group of disorders characterized by defective development of bones and cartilage.
Last Evaluated: May 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:91969832
The term achondrogenesis has been used to characterize the most severe forms of chondrodysplasia in humans, invariably lethal before or shortly after birth. Achondrogenesis type I is a severe chondrodystrophy characterized radiographically by deficient ossification in the lumbar vertebrae and absent ossification in the sacral, pubic and ischial bones and clinically by stillbirth or early death (Maroteaux and Lamy, 1968; Langer et al., 1969). In addition to severe micromelia, there is a disproportionately large cranium due to marked edema of soft tissues. Classification of Achondrogenesis Achondrogenesis was traditionally divided into 2 types: type I (Parenti-Fraccaro) and type II (Langer-Saldino). Borochowitz et al. (1988) suggested that achondrogenesis type I of Parenti-Fraccaro should be classified into 2 distinct disorders: type IA, corresponding to the cases originally published by Houston et al. (1972) and Harris et al. (1972), and type IB (600972), corresponding to the case originally published by Fraccaro (1952). Analysis of the case reported by Parenti (1936) by Borochowitz et al. (1988) suggested the diagnosis of achondrogenesis type II, i.e., the Langer-Saldino type (200610). Type IA would be classified as lethal achondrogenesis, Houston-Harris type; type IB, lethal achondrogenesis, Fraccaro type; and type II, lethal achondrogenesis-hypochondrogenesis, Langer-Saldino type. Superti-Furga (1996) suggested that hypochondrogenesis should be considered separately from achondrogenesis type II because the phenotype can be much milder. Genetic Heterogeneity of Achondrogenesis Achondrogenesis type IB (ACG1B; 600972) is caused by mutation in the DTDST gene (606718), and achondrogenesis type II (ACG2; 200610) is caused by mutation in the COL2A1 gene (120140).
Last Evaluated: May 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:91969832
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:91969832
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
SUN1
Variant:
c.2043G>A
(p.Arg681=)
rsID: rs61744747
Ref Allele: G
Alt Allele: A
Freq: 1.631%uncommon
CADD: 11.28
ClinVar Submissions (1)
Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of joint contractures that begin in early childhood, slowly progressive muscle weakness and wasting initially in a humero-peroneal distribution that later extends to the scapular and pelvic girdle muscles, and cardiac involvement that may manifest as palpitations, presyncope and syncope, poor exercise tolerance, and congestive heart failure. Age of onset, severity, and progression of muscle and cardiac involvement demonstrate both inter- and intrafamilial variability. Clinical variability ranges from early onset with severe presentation in childhood to late onset with slow progression in adulthood. In general, joint contractures appear during the first two decades, followed by muscle weakness and wasting. Cardiac involvement usually occurs after the second decade.
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:869411
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
ENPP1
Variant:
c.-10C>T
rsID: rs750410843
Ref Allele: C
Alt Allele: T
Freq: 1.6334%uncommon
CADD: 8.514
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 08, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:131808026
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
TRIP11
Variant:
c.405T>C
(p.Ala135=)
rsID: rs77981249
Ref Allele: A
Alt Allele: G
Freq: 1.6334%uncommon
CADD: 4.07
ClinVar Submissions (3)
A rare group of disorders characterized by defective development of bones and cartilage.
Last Evaluated: May 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:92021739
The term achondrogenesis has been used to characterize the most severe forms of chondrodysplasia in humans, invariably lethal before or shortly after birth. Achondrogenesis type I is a severe chondrodystrophy characterized radiographically by deficient ossification in the lumbar vertebrae and absent ossification in the sacral, pubic and ischial bones and clinically by stillbirth or early death (Maroteaux and Lamy, 1968; Langer et al., 1969). In addition to severe micromelia, there is a disproportionately large cranium due to marked edema of soft tissues. Classification of Achondrogenesis Achondrogenesis was traditionally divided into 2 types: type I (Parenti-Fraccaro) and type II (Langer-Saldino). Borochowitz et al. (1988) suggested that achondrogenesis type I of Parenti-Fraccaro should be classified into 2 distinct disorders: type IA, corresponding to the cases originally published by Houston et al. (1972) and Harris et al. (1972), and type IB (600972), corresponding to the case originally published by Fraccaro (1952). Analysis of the case reported by Parenti (1936) by Borochowitz et al. (1988) suggested the diagnosis of achondrogenesis type II, i.e., the Langer-Saldino type (200610). Type IA would be classified as lethal achondrogenesis, Houston-Harris type; type IB, lethal achondrogenesis, Fraccaro type; and type II, lethal achondrogenesis-hypochondrogenesis, Langer-Saldino type. Superti-Furga (1996) suggested that hypochondrogenesis should be considered separately from achondrogenesis type II because the phenotype can be much milder. Genetic Heterogeneity of Achondrogenesis Achondrogenesis type IB (ACG1B; 600972) is caused by mutation in the DTDST gene (606718), and achondrogenesis type II (ACG2; 200610) is caused by mutation in the COL2A1 gene (120140).
Last Evaluated: May 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:92021739
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:92021739
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
TRIP11
Variant:
c.-331C>G
rsID: rs1955683
Ref Allele: G
Alt Allele: C
Freq: 1.6366%uncommon
CADD: 15.57
ClinVar Submissions (1)
A rare group of disorders characterized by defective development of bones and cartilage.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 14:92040016
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
TRIP11
Variant:
c.*1374A>C
rsID: rs74801826
Ref Allele: T
Alt Allele: G
Freq: 1.6461%uncommon
CADD: 9.893
ClinVar Submissions (1)
A rare group of disorders characterized by defective development of bones and cartilage.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 14:91968299
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
ABCC6
Variant:
c.473C>T
(p.Ala158Val)
rsID: rs2606921
Ref Allele: G
Alt Allele: A
Freq: 1.666%uncommon
CADD: 10.52
ClinVar Submissions (1)
Pseudoxanthoma elasticum (PXE) is a systemic disorder that affects the elastic tissue of the skin, the eye, and the cardiovascular and gastrointestinal systems. Individuals most commonly present with papules in the skin and/or with angioid streaks of the retina found on routine eye examination or associated with retinal hemorrhage. Rarely, individuals may present with vascular signs and symptoms, such as gastrointestinal bleeding, angina, or intermittent claudication. The most frequent cause of morbidity and disability in PXE is reduced vision from macular hemorrhage and disciform scarring of the macula. Most affected individuals live a normal life span.
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 16:16219555
This individual has one copy of the genetic mutation, and because it's autosomal recessive, they are likely a carrier rather than manifesting the condition. Interpretation of carrier status should be backed by thorough research.
Clinically Significant Pathogenic
Hetero
Gene:
TRDN
Variant:
c.1620A>G
(p.Ile540Met)
rsID: rs7771303
Ref Allele: T
Alt Allele: C
Freq: 1.6692%uncommon
CADD: 0.111
ClinVar Submissions (6)
Last Evaluated: Jun 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:123273341
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by episodic syncope occurring during exercise or acute emotion in individuals without structural cardiac abnormalities. The underlying cause of these episodes is the onset of fast ventricular tachycardia (bidirectional or polymorphic). Spontaneous recovery may occur when these arrhythmias self-terminate. In other instances, ventricular tachycardia may degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation is not readily available. The mean age of onset of symptoms (usually a syncopal episode) is between age seven and twelve years; onset as late as the fourth decade of life has been reported. If untreated, CPVT is highly lethal, as approximately 30% of affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. Sudden death may be the first manifestation of the disease.
Last Evaluated: Jun 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:123273341
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:123273341
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
RIPK4
Variant:
c.*741G>A
rsID: rs13050509
Ref Allele: C
Alt Allele: T
Freq: 1.682%uncommon
CADD: 0.013
ClinVar Submissions (1)
IRF6-related disorders span a spectrum from isolated cleft lip and palate and Van der Woude syndrome (VWS) at the mild end to popliteal pterygium syndrome (PPS) at the more severe end. Individuals with VWS show one or more of the following anomalies: Congenital, usually bilateral, paramedian lower-lip fistulae (pits) or sometimes small mounds with a sinus tract leading from a mucous gland of the lip. Cleft lip (CL). Cleft palate (CP). Note: Cleft lip with or without cleft palate (CL±P) is observed about twice as often as CP only. Submucous cleft palate (SMCP). The PPS phenotype includes the following: CL±P. Fistulae of the lower lip. Webbing of the skin extending from the ischial tuberosities to the heels. In males: bifid scrotum and cryptorchidism. In females: hypoplasia of the labia majora. Syndactyly of fingers and/or toes. Anomalies of the skin around the nails. A characteristic pyramidal fold of skin overlying the nail of the hallux (almost pathognomonic). In some non-classic forms of PPS: filiform synechiae connecting the upper and lower jaws (syngnathia) or the upper and lower eyelids (ankyloblepharon). In both VWS and PPS, growth and intelligence are normal.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 21:41740097
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
OTOA
Variant:
c.2353A>C
(p.Thr785Pro)
rsID: rs464696
Ref Allele: A
Alt Allele: C
Freq: 1.6979%uncommon
CADD: 7.582
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 31, 2015
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 16:21736312
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
TGFBR1
Variant:
c.*4300C>T
rsID: rs41283642
Ref Allele: C
Alt Allele: T
Freq: 1.7059%uncommon
CADD: 15.75
ClinVar Submissions (1)
Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:99153605
Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:99153605
Familial thoracic aortic aneurysm and dissection (familial TAAD) involves problems with the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. Familial TAAD affects the upper part of the aorta, near the heart. This part of the aorta is called the thoracic aorta because it is located in the chest (thorax). Other vessels that carry blood from the heart to the rest of the body (arteries) can also be affected.In familial TAAD, the aorta can become weakened and stretched (aortic dilatation), which can lead to a bulge in the blood vessel wall (an aneurysm). Aortic dilatation may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection), allowing blood to flow abnormally between the layers. These aortic abnormalities are potentially life-threatening because they can decrease blood flow to other parts of the body such as the brain or other vital organs, or cause the aorta to break open (rupture).The occurrence and timing of these aortic abnormalities vary, even within the same affected family. They can begin in childhood or not occur until late in life. Aortic dilatation is generally the first feature of familial TAAD to develop, although in some affected individuals dissection occurs with little or no aortic dilatation.Aortic aneurysms usually have no symptoms. However, depending on the size, growth rate, and location of these abnormalities, they can cause pain in the jaw, neck, chest, or back; swelling in the arms, neck, or head; difficult or painful swallowing; hoarseness; shortness of breath; wheezing; a chronic cough; or coughing up blood. Aortic dissections usually cause severe, sudden chest or back pain, and may also result in unusually pale skin (pallor), a very faint pulse, numbness or tingling (paresthesias) in one or more limbs, or paralysis.Familial TAAD may not be associated with other signs and symptoms. However, some individuals in affected families show mild features of related conditions called Marfan syndrome or Loeys-Dietz syndrome. These features include tall stature, stretch marks on the skin, an unusually large range of joint movement (joint hypermobility), and either a sunken or protruding chest. Occasionally, people with familial TAAD develop aneurysms in the brain or in the section of the aorta located in the abdomen (abdominal aorta). Some people with familial TAAD have heart abnormalities that are present from birth (congenital). Affected individuals may also have a soft out-pouching in the lower abdomen (inguinal hernia), an abnormal curvature of the spine (scoliosis), or a purplish skin discoloration (livedo reticularis) caused by abnormalities in the tiny blood vessels of the skin (dermal capillaries). However, these conditions are also common in the general population. Depending on the genetic cause of familial TAAD in particular families, they may have an increased risk of developing blockages in smaller arteries, which can lead to heart attack and stroke.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:99153605
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
AGPAT2
Variant:
c.*535C>T
rsID: rs138670030
Ref Allele: G
Alt Allele: A
Freq: 1.7982%uncommon
CADD: 2.6
ClinVar Submissions (1)
Berardinelli-Seip congenital lipodystrophy (BSCL) is usually diagnosed at birth or soon thereafter. Because of the absence of functional adipocytes, lipid is stored in other tissues, including muscle and liver. Affected individuals develop insulin resistance and approximately 25%-35% develop diabetes mellitus between ages 15 and 20 years. Hepatomegaly secondary to hepatic steatosis and skeletal muscle hypertrophy occur in all affected individuals. Hypertrophic cardiomyopathy is reported in 20%-25% of affected individuals and is a significant cause of morbidity from cardiac failure and early mortality.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:136673217
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
GPR179
Variant:
c.5930C>A
(p.Pro1977His)
rsID: rs62073368
Ref Allele: G
Alt Allele: T
Freq: 1.811%uncommon
CADD: 22.2
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:38327639
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
IL2RA
Variant:
c.*70G>A
rsID: rs12722600
Ref Allele: C
Alt Allele: T
Freq: 1.8205%uncommon
CADD: 0.173
ClinVar Submissions (1)
Immunodeficiency-41 is an autosomal recessive complex disorder of immune dysregulation. Affected individuals present in infancy with recurrent viral, fungal, and bacterial infections, lymphadenopathy, and variable autoimmune features, such as autoimmune enteropathy and eczematous skin lesions. Immunologic studies show a defect in T-cell regulation (summary by Goudy et al., 2013).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 10:6012802
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
FANCM
Variant:
c.3758A>G
(p.Asn1253Ser)
rsID: rs45604036
Ref Allele: A
Alt Allele: G
Freq: 1.8564%uncommon
CADD: 0.055
ClinVar Submissions (3)
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract – are more common in individuals with FA.
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:45176512
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:45176512
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
TMEM138
Variant:
c.261G>A
(p.Val87=)
rsID: rs35245221
Ref Allele: G
Alt Allele: A
Freq: 1.8651%uncommon
CADD: 16.74
ClinVar Submissions (7)
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Last Evaluated: Sep 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:61366177
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Last Evaluated: Sep 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:61366177
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:61366177
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
UBR1
Variant:
c.2695A>G
(p.Ile899Val)
rsID: rs35069201
Ref Allele: T
Alt Allele: C
Freq: 1.8659%uncommon
CADD: 6.651
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 15:43024873
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
OTOA
Variant:
c.2359G>T
(p.Glu787Ter)
rsID: rs200988634
Ref Allele: G
Alt Allele: T
Freq: 1.8731%uncommon
CADD: 38
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 05, 2015
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 16:21736318
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
CHST3
Variant:
c.*1101T>G
rsID: rs116999241
Ref Allele: T
Alt Allele: G
Freq: 1.8739%uncommon
CADD: 7.724
ClinVar Submissions (1)
Larsen syndrome is a disorder that affects the development of bones throughout the body. The signs and symptoms of Larsen syndrome vary widely even within the same family. Affected individuals are usually born with inward- and upward-turning feet (clubfeet) and dislocations of the hips, knees, and elbows. They generally have small extra bones in their wrists and ankles that are visible on x-ray images. The tips of their fingers, especially the thumbs, are typically blunt and square-shaped (spatulate).People with Larsen syndrome may also have an unusually large range of joint movement (hypermobility) and short stature. They can also have abnormal curvature of the spine (kyphosis or scoliosis) that may compress the spinal cord and lead to weakness of the limbs.Characteristic facial features include a prominent forehead (frontal bossing), flattening of the bridge of the nose and of the middle of the face (midface hypoplasia), and wide-set eyes (ocular hypertelorism). Some people with Larsen syndrome have an opening in the roof of the mouth (a cleft palate) or hearing loss caused by malformations in the tiny bones in the ears (ossicles). Some affected individuals experience respiratory problems as a result of weakness of the airways that can lead to partial closing, short pauses in breathing (apnea), and frequent respiratory infections. People with Larsen syndrome can survive into adulthood and intelligence is unaffected.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 10:72009572
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 10:72009572
Spondyloepiphyseal dysplasia congenita is an autosomal dominant chondrodysplasia characterized by disproportionate short stature (short trunk), abnormal epiphyses, and flattened vertebral bodies. Skeletal features are manifested at birth and evolve with time. Other features include myopia and/or retinal degeneration with retinal detachment and cleft palate (summary by Anderson et al., 1990).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 10:72009572
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 10:72009572
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
ERMARD
Variant:
c.1944A>G
(p.Thr648=)
rsID: rs2274952
Ref Allele: A
Alt Allele: G
Freq: 1.889%uncommon
CADD: 0.381
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 24, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:169781420
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
CPS1
Variant:
c.*754T>G
rsID: rs73078125
Ref Allele: T
Alt Allele: G
Freq: 1.8914%uncommon
CADD: 6.825
ClinVar Submissions (1)
Carbamoyl phosphate synthetase I deficiency is an autosomal recessive inborn error of metabolism of the urea cycle which causes hyperammonemia. There are 2 main forms: a lethal neonatal type and a less severe, delayed-onset type (summary by Klaus et al., 2009). Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis. Five disorders involving different defects in the biosynthesis of the enzymes of the urea cycle have been described: ornithine transcarbamylase deficiency (311250), carbamyl phosphate synthetase deficiency, argininosuccinate synthetase deficiency, or citrullinemia (215700), argininosuccinate lyase deficiency (207900), and arginase deficiency (207800).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:210678739
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
BRCA1
Variant:
c.135-2555C>G
rsID: rs8176121
Ref Allele: G
Alt Allele: C
Freq: 1.9002%uncommon
CADD: 1.746
ClinVar Submissions (1)
BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The exact cancer risks differ slightly depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant.
Last Evaluated: Jan 12, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:43109088
Expert Reviewed Benign
Hetero
Gene:
TBC1D24
Variant:
c.*2395A>G
rsID: rs11543247
Ref Allele: A
Alt Allele: G
Freq: 1.9073%uncommon
CADD: 3.842
ClinVar Submissions (1)
TBC1D24-related disorders comprise a continuum of features that were originally described as distinct, recognized phenotypes: DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures). Profound sensorineural hearing loss, onychodystrophy, osteodystrophy, intellectual disability / developmental delay, and seizures. Familial infantile myoclonic epilepsy (FIME). Early-onset myoclonic seizures, focal epilepsy, dysarthria, and mild-to-moderate intellectual disability. Progressive myoclonus epilepsy (PME). Action myoclonus, tonic-clonic seizures, progressive neurologic decline, and ataxia. Early-infantile epileptic encephalopathy 16 (EIEE16). Epileptiform EEG abnormalities which themselves are believed to contribute to progressive disturbance in cerebral function. Autosomal recessive nonsyndromic hearing loss, DFNB86. Profound prelingual deafness. Autosomal dominant nonsyndromic hearing loss, DFNA65. Slowly progressive deafness with onset in the third decade, initially affecting the high frequencies.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 16:2503353
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
GFPT1
Variant:
c.675C>T
(p.Leu225=)
rsID: rs78952091
Ref Allele: G
Alt Allele: A
Freq: 1.9105%uncommon
CADD: 1.914
ClinVar Submissions (5)
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:69354499
Congenital myasthenic syndrome-12 is an autosomal recessive neuromuscular disorder characterized by onset of proximal muscle weakness in the first decade. EMG classically shows a decremental response to repeated nerve stimulation. Affected individuals show a favorable response to acetylcholinesterase (AChE) inhibitors (summary by Senderek et al., 2011). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:69354499
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:69354499
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
AGRN
Variant:
c.729C>G
(p.Gly243=)
rsID: rs191270495
Ref Allele: C
Alt Allele: G
Freq: 1.9169%uncommon
CADD: 6.579
ClinVar Submissions (4)
Congenital myasthenic syndromes (designated as CMS throughout this entry) are characterized by fatigable weakness of skeletal muscle (e.g., ocular, bulbar, limb muscles) with onset at or shortly after birth or in early childhood; rarely, symptoms may not manifest until later in childhood. Cardiac and smooth muscle are usually not involved. Severity and course of disease are highly variable, ranging from minor symptoms to progressive disabling weakness. In some subtypes of CMS, myasthenic symptoms may be mild, but sudden severe exacerbations of weakness or even sudden episodes of respiratory insufficiency may be precipitated by fever, infections, or excitement. Major findings of the neonatal-onset subtype include: respiratory insufficiency with sudden apnea and cyanosis; feeding difficulties; poor suck and cry; choking spells; eyelid ptosis; and facial, bulbar, and generalized weakness. Arthrogryposis multiplex congenita may also be present. Stridor in infancy may be an important clue to CMS. Later childhood-onset subtypes show abnormal muscle fatigability with difficulty in activities such as running or climbing stairs; motor milestones may be delayed; fluctuating eyelid ptosis and fixed or fluctuating extraocular muscle weakness are common presentations.
Last Evaluated: Mar 27, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:1041174
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Mar 27, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:1041174
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 27, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:1041174
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
SPEF2
Variant:
c.1983T>C
(p.Asn661=)
rsID: rs78576797
Ref Allele: T
Alt Allele: C
Freq: 1.9169%uncommon
CADD: 0.511
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 29, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:35695742
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
FSHR
Variant:
c.*246T>A
rsID: rs72825259
Ref Allele: A
Alt Allele: T
Freq: 1.94%uncommon
CADD: 5.466
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:48962487
A complication of OVULATION INDUCTION in infertility treatment. It is graded by the severity of symptoms which include OVARY enlargement, multiple OVARIAN FOLLICLES; OVARIAN CYSTS; ASCITES; and generalized EDEMA. The full-blown syndrome may lead to RENAL FAILURE, respiratory distress, and even DEATH. Increased capillary permeability is caused by the vasoactive substances, such as VASCULAR ENDOTHELIAL GROWTH FACTORS, secreted by the overly-stimulated OVARIES.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:48962487
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
CHRM2
Variant:
c.-130C>T
rsID: rs77128879
Ref Allele: C
Alt Allele: T
Freq: 1.948%uncommon
CADD: 7.504
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 19, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:136869413
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
CDH13
Variant:
c.257A>G
(p.Asn86Ser)
rsID: rs72807847
Ref Allele: A
Alt Allele: G
Freq: 1.9687%uncommon
CADD: 11.02
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:82858432
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
PFKM
Variant:
c.1342-14G>T
rsID: rs56117548
Ref Allele: G
Alt Allele: T
Freq: 1.9695%uncommon
CADD: 5.813
ClinVar Submissions (4)
Glycogen storage disease VII is an autosomal recessive metabolic disorder characterized clinically by exercise intolerance, muscle cramping, exertional myopathy, and compensated hemolysis. Myoglobinuria may also occur. The deficiency of the muscle isoform of PFK results in a total and partial loss of muscle and red cell PFK activity, respectively. Raben and Sherman (1995) noted that not all patients with GSD VII seek medical care because in some cases it is a relatively mild disorder.
Last Evaluated: Mar 23, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:48141297
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Mar 23, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:48141297
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 23, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:48141297
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
FECH
Variant:
c.163G>T
(p.Gly55Cys)
rsID: rs3848519
Ref Allele: C
Alt Allele: A
Freq: 1.9742%uncommon
CADD: 14.57
ClinVar Submissions (3)
Erythropoietic protoporphyria (EPP) is characterized by cutaneous photosensitivity (usually beginning in infancy or childhood) that results in tingling, burning, pain, and itching within 30 minutes after exposure to sun or ultraviolet light and may be accompanied by swelling and redness. Symptoms (which may seem out of proportion to the visible skin lesions) may persist for hours or days after the initial phototoxic reaction. Photosensitivity remains for life. Multiple episodes of acute photosensitivity may lead to chronic changes of sun-exposed skin (lichenification, leathery pseudovesicles, grooving around the lips) and loss of lunulae of the nails. Approximately 20%-30% of individuals with EPP have some degree of liver dysfunction, which is typically mild with slight elevations of the liver enzymes. Up to 5% may develop more advanced liver disease which may be accompanied by motor neuropathy similar to that seen in the acute porphyrias.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57580104
OMIM Allelic Variant: 612386.0001
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57580104
OMIM Allelic Variant: 612386.0001
This individual has one copy of the genetic mutation, and because it's autosomal recessive, they are likely a carrier rather than manifesting the condition. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
AFG3L2
Variant:
c.1026+8G>A
rsID: rs8091858
Ref Allele: C
Alt Allele: T
Freq: 2.026%uncommon
CADD: 4.442
ClinVar Submissions (4)
Autosomal dominant cerebellar ataxia (ADCA) describes a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by a slowly progressive ataxia of gait, stance and limbs, dysarthria and/or oculomotor disorder, due to cerebellar degeneration in the absence of coexisting diseases. The degenerative process can be limited to the cerebellum (ADCA type 3) or may additionally involve the retina (ADCA type 2), optic nerve, ponto-medullary systems, basal ganglia, cerebral cortex, spinal tracts or peripheral nerves (ADCA type 1) (see these terms). In ACDA type 4 (see this term), a cerebellar syndrome is associated with epilepsy.
Last Evaluated: Jul 12, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 18:12358662
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 12, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 18:12358662
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 12, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 18:12358662
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
CASP8
Variant:
c.*411G>C
rsID: rs17860432
Ref Allele: G
Alt Allele: C
Freq: 2.0563%uncommon
CADD: 1.226
ClinVar Submissions (1)
Caspase 8 deficiency is a syndrome of lymphadenopathy and splenomegaly, marginal elevation of 'double-negative T cells' (DNT; T-cell receptor alpha/beta+, CD4-/CD8-), defective FAS-induced apoptosis, and defective T-, B-, and natural killer (NK)-cell activation, with recurrent bacterial and viral infections (summary by Madkaikar et al., 2011).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:201287005
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
MAN1B1
Variant:
c.590C>T
(p.Pro197Leu)
rsID: rs61744585
Ref Allele: C
Alt Allele: T
Freq: 2.0778%uncommon
CADD: 2.7
ClinVar Submissions (5)
Last Evaluated: Jul 24, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:137096361
Last Evaluated: Jul 24, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:137096361
Last Evaluated: Jul 24, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:137096361
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 24, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:137096361
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
TMC8
Variant:
c.669-4G>C
rsID: rs8079824
Ref Allele: G
Alt Allele: C
Freq: 2.0794%uncommon
CADD: 7.524
ClinVar Submissions (1)
Epidermodysplasia verruciformis (EV) is a rare genodermatosis associated with a high risk of skin cancer. EV results from an abnormal susceptibility to specific related human papillomavirus (HPV) genotypes and to the oncogenic potential of some of them, mainly HPV5. Infection with EV-associated HPV leads to the early development of disseminated flat wart-like and pityriasis versicolor-like lesions. Patients are unable to reject their lesions, and cutaneous Bowen carcinomas in situ and invasive squamous cell carcinomas develop in about half of them, mainly on sun-exposed areas (summary by Ramoz et al., 2000). Genetic Heterogeneity of Susceptibility to Epidermodysplasia Verruciformis Susceptibility to EV2 (618231) is conferred by mutation in the TMC8 gene (605829) on chromosome 17q25; EV3 (618267) by mutation in the CIB1 gene (602293) on chromosome 15q26; EV4 (618307) by mutation in the RHOH gene (602037) on chromosome 4p13; and EV5 (618309) by mutation in the IL7 gene (146660) on chromosome 8q12.
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:78133849
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
CP
Variant:
c.1652C>T
(p.Thr551Ile)
rsID: rs61733458
Ref Allele: G
Alt Allele: A
Freq: 2.0913%uncommon
CADD: 26.1
ClinVar Submissions (7)
Aceruloplasminemia is characterized by iron accumulation in the brain and viscera. The clinical triad of retinal degeneration, diabetes mellitus (DM), and neurologic disease is seen in individuals ranging from age 30 years to older than 70 years. The neurologic findings of movement disorder (blepharospasm, grimacing, facial and neck dystonia, tremors, chorea) and ataxia (gait ataxia, dysarthria) correspond to regions of iron deposition in the brain. Individuals with aceruloplasminemia often present with anemia prior to onset of DM or obvious neurologic problems. Cognitive dysfunction including apathy and forgetfulness occurs in more than half of individuals with this condition.
Last Evaluated: Jul 27, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:149198428
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 27, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:149198428
This individual has one copy of the genetic mutation, and because it's autosomal recessive, they are likely a carrier rather than manifesting the condition. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
MYH3
Variant:
c.3008C>T
(p.Ala1003Val)
rsID: rs34088014
Ref Allele: G
Alt Allele: A
Freq: 2.0913%uncommon
CADD: 23.5
ClinVar Submissions (3)
A non-progressive finding characterized by multiple joint contractures found throughout the body at birth.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10639392
Freeman-Sheldon syndrome (FSS), or DA2A, is phenotypically similar to DA1. In addition to contractures of the hands and feet, FSS is characterized by oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice (often only a few millimeters in diameter at birth), puckered lips, and an H-shaped dimple of the chin; hence, FSS has been called 'whistling face syndrome.' The limb phenotypes of DA1 and FSS may be so similar that they can only be distinguished by the differences in facial morphology (summary by Bamshad et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10639392
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10639392
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
MYH3
Variant:
c.5254G>A
(p.Ala1752Thr)
rsID: rs34393601
Ref Allele: C
Alt Allele: T
Freq: 2.0961%uncommon
CADD: 23.9
ClinVar Submissions (3)
A non-progressive finding characterized by multiple joint contractures found throughout the body at birth.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10631643
Freeman-Sheldon syndrome (FSS), or DA2A, is phenotypically similar to DA1. In addition to contractures of the hands and feet, FSS is characterized by oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice (often only a few millimeters in diameter at birth), puckered lips, and an H-shaped dimple of the chin; hence, FSS has been called 'whistling face syndrome.' The limb phenotypes of DA1 and FSS may be so similar that they can only be distinguished by the differences in facial morphology (summary by Bamshad et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10631643
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10631643
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
AGRN
Variant:
c.2457G>C
(p.Gly819=)
rsID: rs112039851
Ref Allele: G
Alt Allele: C
Freq: 2.1009%uncommon
CADD: 5.656
ClinVar Submissions (4)
Congenital myasthenic syndromes (designated as CMS throughout this entry) are characterized by fatigable weakness of skeletal muscle (e.g., ocular, bulbar, limb muscles) with onset at or shortly after birth or in early childhood; rarely, symptoms may not manifest until later in childhood. Cardiac and smooth muscle are usually not involved. Severity and course of disease are highly variable, ranging from minor symptoms to progressive disabling weakness. In some subtypes of CMS, myasthenic symptoms may be mild, but sudden severe exacerbations of weakness or even sudden episodes of respiratory insufficiency may be precipitated by fever, infections, or excitement. Major findings of the neonatal-onset subtype include: respiratory insufficiency with sudden apnea and cyanosis; feeding difficulties; poor suck and cry; choking spells; eyelid ptosis; and facial, bulbar, and generalized weakness. Arthrogryposis multiplex congenita may also be present. Stridor in infancy may be an important clue to CMS. Later childhood-onset subtypes show abnormal muscle fatigability with difficulty in activities such as running or climbing stairs; motor milestones may be delayed; fluctuating eyelid ptosis and fixed or fluctuating extraocular muscle weakness are common presentations.
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:1045444
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:1045444
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
MYH3
Variant:
c.6T>C
(p.Ser2=)
rsID: rs17817203
Ref Allele: A
Alt Allele: G
Freq: 2.1279%uncommon
CADD: 10.25
ClinVar Submissions (3)
A non-progressive finding characterized by multiple joint contractures found throughout the body at birth.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10655059
Freeman-Sheldon syndrome (FSS), or DA2A, is phenotypically similar to DA1. In addition to contractures of the hands and feet, FSS is characterized by oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice (often only a few millimeters in diameter at birth), puckered lips, and an H-shaped dimple of the chin; hence, FSS has been called 'whistling face syndrome.' The limb phenotypes of DA1 and FSS may be so similar that they can only be distinguished by the differences in facial morphology (summary by Bamshad et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10655059
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10655059
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
MPL
Variant:
c.340G>A
(p.Val114Met)
rsID: rs12731981
Ref Allele: G
Alt Allele: A
Freq: 2.1678%uncommon
CADD: 18.86
ClinVar Submissions (5)
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare disorder expressed in infancy and characterized by isolated thrombocytopenia and megakaryocytopenia with no physical anomalies (Muraoka et al., 1997). King et al. (2005) proposed a new classification of CAMT based on the course and outcome of the disease, as exemplified by 20 patients: CAMT type I (11 patients) was characterized by early onset of severe pancytopenia, decreased bone marrow activity, and very low platelet counts. CAMT type II (9 patients) was somewhat milder and characterized by transient increases of platelet counts up to nearly normal values during the first year of life and an onset of bone marrow failure at age 3 or later.
Last Evaluated: Jun 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:43338669
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare disorder expressed in infancy and characterized by isolated thrombocytopenia and megakaryocytopenia with no physical anomalies (Muraoka et al., 1997). King et al. (2005) proposed a new classification of CAMT based on the course and outcome of the disease, as exemplified by 20 patients: CAMT type I (11 patients) was characterized by early onset of severe pancytopenia, decreased bone marrow activity, and very low platelet counts. CAMT type II (9 patients) was somewhat milder and characterized by transient increases of platelet counts up to nearly normal values during the first year of life and an onset of bone marrow failure at age 3 or later.
Last Evaluated: Jun 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:43338669
Thrombocythemia, or thrombocytosis, is a myeloproliferative disorder characterized by excessive platelet production resulting in increased numbers of circulating platelets. Thrombocythemia can be associated with thrombotic or hemorrhagic episodes and occasional leukemic transformation (summary by Wiestner et al., 1998). Genetic Heterogeneity of Thrombocythemia THCYT2 (601977) is caused by germline or somatic mutation in the THPO receptor gene (MPL; 159530) on chromosome 1p34; THCYT3 (614521) is caused by germline or somatic mutation in the JAK2 gene (147796) on chromosome 9p; and a possible X-linked form (THCYTX; 300331) has been reported. Somatic mutations in the TET2 (612839), ASXL1 (612990), SH2B3 (605093), and SF3B1 (605590) genes have also been found in cases of essential thrombocythemia. Somatic mutation in the CALR gene (109091) occurs in approximately 70% of essential thrombocythemia patients who lack JAK2 and MPL mutations (Klampfl et al., 2013; Nangalia et al., 2013).
Last Evaluated: Jun 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:43338669
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:43338669
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Insufficiently evaluated benign — A study in 2001 reported an association with Congenital Amegakaryocytic Thrombocytopenia, but a report in 2009 reclassified it as a benign polymorphism.
Benign/Likely benign
Hetero
Gene:
LIMS2
Variant:
c.261C>T
(p.Tyr87=)
rsID: rs35765118
Ref Allele: G
Alt Allele: A
Freq: 2.1757%uncommon
CADD: 20.8
ClinVar Submissions (2)
Autosomal recessive muscular dystrophy with cardiomyopathy and triangular tongue (MDRCMTT) is an autosomal recessive muscle disorder characterized by onset of severe and progressive muscle weakness and atrophy in childhood, resulting in loss of independent ambulation. Patients may also have dilated cardiomyopathy and have macroglossia with a small tip, resulting in a triangular appearance of the tongue (summary by Warman Chardon et al., 2015).
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:127654879
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:127654879
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
RANBP2
Variant:
c.-45C>T
rsID: rs79379002
Ref Allele: C
Alt Allele: T
Freq: 2.2084%uncommon
CADD: 12.01
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 29, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:108719562
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
TEK
Variant:
c.*381C>G
rsID: rs10967789
Ref Allele: C
Alt Allele: G
Freq: 2.2092%uncommon
CADD: 4.645
ClinVar Submissions (1)
The condition multiple cutaneous and mucosal venous malformations (VMCM) is characterized by the presence of small, multifocal bluish cutaneous and/or mucosal venous malformations. They are usually present at birth. New lesions appear with time. Small lesions are usually asymptomatic; larger lesions can invade subcutaneous muscle and cause pain. Malignant transformation has not been reported.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:27229613
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
ATM
Variant:
c.4138C>T
(p.His1380Tyr)
rsID: rs3092856
Ref Allele: C
Alt Allele: T
Freq: 2.2386%uncommon
CADD: 10.96
ClinVar Submissions (10)
Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Chromosomal breakage is a feature. AT cells are abnormally sensitive to killing by ionizing radiation (IR), and abnormally resistant to inhibition of DNA synthesis by ionizing radiation. The latter trait has been used to identify complementation groups for the classic form of the disease (Jaspers et al., 1988). At least 4 of these (A, C, D, and E) map to chromosome 11q23 (Sanal et al., 1990) and are associated with mutations in the ATM gene.
Last Evaluated: Jan 13, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 10
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:108289005
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Jan 13, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 10
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:108289005
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 13, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 10
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:108289005
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 13, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 10
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:108289005
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
ATM
Variant:
c.2639-17G>T
rsID: rs2234994
Ref Allele: G
Alt Allele: T
Freq: 2.2402%uncommon
CADD: 3.351
ClinVar Submissions (4)
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Feb 04, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:108268393
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 04, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:108268393
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
FTO
Variant:
c.*2301G>A
rsID: rs79234192
Ref Allele: G
Alt Allele: A
Freq: 2.2498%uncommon
CADD: 5.383
ClinVar Submissions (1)
Growth retardation, developmental delay, and facial dysmorphism (GDFD) is an autosomal recessive multiple congenital anomaly syndrome characterized by severe psychomotor retardation, poor overall growth, and dysmorphic facial features. Additional features may include cardiac malformations and deafness (summary by Daoud et al., 2016).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 16:54114216
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
PAX5
Variant:
c.1029G>A
(p.Gly343=)
rsID: rs35469494
Ref Allele: C
Alt Allele: T
Freq: 2.2808%uncommon
CADD: 7.763
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 19, 2013
Review Status: no assertion provided
Number of Submitters: 1
Clinical Significance: not provided
Assembly: GRCh38
Chromosome/Position: 9:36846913
Hetero
Gene:
AGRN
Variant:
c.2254+16G>A
rsID: rs114389542
Ref Allele: G
Alt Allele: A
Freq: 2.2936%uncommon
CADD: 1.589
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 31, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:1044455
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
EP300
Variant:
c.2131+18T>A
rsID: rs9611506
Ref Allele: T
Alt Allele: A
Freq: 2.3023%uncommon
CADD: 0.83
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 09, 2014
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 22:41146834
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
ATM
Variant:
c.*2199C>G
rsID: rs75959910
Ref Allele: C
Alt Allele: G
Freq: 2.3087%uncommon
CADD: 2.256
ClinVar Submissions (1)
Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Chromosomal breakage is a feature. AT cells are abnormally sensitive to killing by ionizing radiation (IR), and abnormally resistant to inhibition of DNA synthesis by ionizing radiation. The latter trait has been used to identify complementation groups for the classic form of the disease (Jaspers et al., 1988). At least 4 of these (A, C, D, and E) map to chromosome 11q23 (Sanal et al., 1990) and are associated with mutations in the ATM gene.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:108367707
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
ATM
Variant:
c.*2220A>G
rsID: rs75293772
Ref Allele: A
Alt Allele: G
Freq: 2.3087%uncommon
CADD: 11.16
ClinVar Submissions (1)
Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Chromosomal breakage is a feature. AT cells are abnormally sensitive to killing by ionizing radiation (IR), and abnormally resistant to inhibition of DNA synthesis by ionizing radiation. The latter trait has been used to identify complementation groups for the classic form of the disease (Jaspers et al., 1988). At least 4 of these (A, C, D, and E) map to chromosome 11q23 (Sanal et al., 1990) and are associated with mutations in the ATM gene.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:108367728
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
LPL
Variant:
c.106G>A
(p.Asp36Asn)
rsID: rs1801177
Ref Allele: G
Alt Allele: A
Freq: 2.3366%uncommon
CADD: 15.36
ClinVar Submissions (5)
An imbalance between myocardial functional requirements and the capacity of the CORONARY VESSELS to supply sufficient blood flow. It is a form of MYOCARDIAL ISCHEMIA (insufficient blood supply to the heart muscle) caused by a decreased capacity of the coronary vessels.
Last Evaluated: Jun 13, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 8:19948197
OMIM Allelic Variant: 609708.0035
APOE p.Leu167del is a rare genetic variant described in 38 cases in the literature with a range of clinical phenotypes. Three phenotypes can be associated with the APOE p.Leu167del variant: Inherited lipemic splenomegaly (also known as sea-blue histiocytosis) characterized by hypertriglyceridemia and splenomegaly. Variable manifestations include thrombocytopenia, liver function abnormalities, and cardiovascular disease. Autosomal dominant hypercholesterolemia (ADH) characterized by markedly elevated LDL cholesterol levels that leads to premature morbidity and mortality from atherosclerotic cardiovascular disease (ASCVD). Familial combined hyperlipidemia (FCHL) characterized by variable elevations of total cholesterol, triglycerides, or LDL cholesterol and a high risk of premature ASCVD. It has been suggested that the phenotype associated with the APOE p.Leu167del variant may depend on multiple factors, including sex, APOE genotype, control of hyperlipidemia, gene-gene interactions, gene-environment interactions, or perhaps epigenetic and other non-Mendelian effects.
Last Evaluated: Jun 13, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 8:19948197
OMIM Allelic Variant: 609708.0035
Familial lipoprotein lipase (LPL) deficiency usually presents in childhood and is characterized by very severe hypertriglyceridemia with episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. Clearance of chylomicrons from the plasma is impaired, causing triglycerides to accumulate in plasma and the plasma to have a milky (lactescent or lipemic) appearance. Symptoms usually resolve with restriction of total dietary fat to =20 g/day.
Last Evaluated: Jun 13, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 8:19948197
OMIM Allelic Variant: 609708.0035
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 13, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 8:19948197
OMIM Allelic Variant: 609708.0035
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 13, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 8:19948197
OMIM Allelic Variant: 609708.0035
This individual has one copy of the genetic mutation, and depending on the condition, this mutation can act as either autosomal dominant or recessive. Thus, they might manifest one condition while being a carrier for another. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
KCNH5
Variant:
c.2088G>A
(p.Val696=)
rsID: rs36004050
Ref Allele: C
Alt Allele: T
Freq: 2.3541%uncommon
CADD: 7.874
ClinVar Submissions (1)
A neurological disorder characterized by recurring seizures presenting within the first three months of life and progressive cerebral dysfunction.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 14:62708387
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
ALS2
Variant:
c.3885G>A
(p.Ala1295=)
rsID: rs34946105
Ref Allele: C
Alt Allele: T
Freq: 2.3581%uncommon
CADD: 5.414
ClinVar Submissions (3)
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:201715791
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:201715791
ALS2-related disorders involve retrograde degeneration of the upper motor neurons of the pyramidal tracts and comprise a clinical continuum from infantile ascending hereditary spastic paraplegia (IAHSP), to juvenile forms without lower motor neuron involvement (juvenile primary lateral sclerosis [JPLS]), to forms with lower motor neuron involvement (autosomal recessive juvenile amyotrophic lateral sclerosis [JALS]). IAHSP is characterized by onset of spasticity with increased reflexes and sustained clonus of the lower limbs within the first two years of life, progressive weakness and spasticity of the upper limbs by age seven to eight years, and wheelchair dependence in the second decade with progression toward severe spastic tetraparesis and a pseudobulbar syndrome. JPLS is characterized by onset and loss of ability to walk during the second year of life, progressive signs of upper motor neuron disease, wheelchair dependence by adolescence, and later loss of motor speech production. JALS is characterized by onset during childhood (mean age of onset 6.5 years), spasticity of facial muscles, uncontrolled laughter, spastic dysarthria, spastic gait, moderate muscle atrophy (variably present), bladder dysfunction, and sensory disturbances; some individuals are bedridden by age 12 to 50 years.
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:201715791
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:201715791
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
TNFSF11
Variant:
c.*383C>T
rsID: rs9567000
Ref Allele: C
Alt Allele: T
Freq: 2.3613%uncommon
CADD: 10.06
ClinVar Submissions (1)
A rare genetic disorder inherited in an autosomal dominant, autosomal recessive, or X-linked recessive pattern. In the majority of cases it is caused by mutations in the CLCN7, TCIRG1, or IKBKG genes. It is characterized by excessive bone formation due to the failure of osteoclasts to resorb bone. It manifests with deformities, fractures, hepatosplenomegaly, anemia, and extramedullary hematopoiesis.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 13:42607301
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
FBXL4
Variant:
c.105T>A
(p.His35Gln)
rsID: rs34316889
Ref Allele: A
Alt Allele: T
Freq: 2.3884%uncommon
CADD: 12.65
ClinVar Submissions (4)
FBXL4-related encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome is a multi-system disorder characterized primarily by congenital or early-onset lactic acidosis and growth failure, feeding difficulty, hypotonia, and developmental delay. Other neurologic manifestations can include seizures, movement disorders, ataxia, autonomic dysfunction, and stroke-like episodes. All affected individuals alive at the time they were reported (median age: 3.5 years) demonstrated significant developmental delay. Other findings can involve the heart (hypertrophic cardiomyopathy, congenital heart malformations, arrhythmias), liver (mildly elevated transaminases), eyes (cataract, strabismus, nystagmus, optic atrophy), hearing (sensorineural hearing loss), and bone marrow (neutropenia, lymphopenia). Survival varies; the median age of reported deaths was two years (range 2 days - 75 months), although surviving individuals as old as 36 years have been reported. To date FBXL4-related mtDNA depletion syndrome has been reported in 50 individuals.
Last Evaluated: Dec 29, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:98926884
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 29, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:98926884
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 29, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:98926884
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
AK1
Variant:
c.367G>C
(p.Glu123Gln)
rsID: rs8192462
Ref Allele: C
Alt Allele: G
Freq: 2.3891%uncommon
CADD: 23.1
ClinVar Submissions (2)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 27, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:127868470
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 27, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:127868470
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
KRT5
Variant:
c.-73T>C
rsID: rs3741725
Ref Allele: A
Alt Allele: G
Freq: 2.3923%uncommon
CADD: 9.262
ClinVar Submissions (1)
Epidermolysis bullosa simplex (EBS) is characterized by fragility of the skin (and mucosal epithelia in some cases) that results in non-scarring blisters and erosions caused by minor mechanical trauma. The current classification of epidermolysis bullosa (EB) includes two major types and 17 minor subtypes of EBS; all share the common feature of blistering above the dermal-epidermal junction at the ultrastructural level. The four most common subtypes of EBS are the focus of this GeneReview: EBS, localized (EBS-loc; previously known as Weber-Cockayne type). EBS, generalized intermediate (EBS-gen intermed; previously known as Koebner type). EBS-with mottled pigmentation (EBS-MP). EBS, generalized severe (EBS-gen sev; previously known as Dowling-Meara type). The phenotypes for these subtypes range from relatively mild blistering of the hands and feet to more generalized blistering, which can be fatal. In EBS-loc, blisters are rarely present or minimal at birth and may occur on the knees and shins with crawling or on the feet at approximately age 18 months; some individuals manifest the disease in adolescence or early adulthood. Blisters are usually confined to the hands and feet, but can occur anywhere if trauma is significant. In EBS, gen intermed, blisters may be present at birth or develop within the first few months of life. Involvement is more widespread than in EBS-loc, but generally milder than in EBS-gen sev. In EBS-MP, skin fragility is evident at birth and clinically indistinguishable from EBS-gen sev; over time, progressive brown pigmentation interspersed with hypopigmented spots develops on the trunk and extremities, with the pigmentation disappearing in adult life. Focal palmar and plantar hyperkeratoses may occur. In EBS-gen sev, onset is usually at birth; severity varies greatly, both among and within families. Widespread and severe blistering and/or multiple grouped clumps of small blisters are typical and hemorrhagic blisters are common. Improvement occurs during mid- to late childhood. Progressive hyperkeratosis of the palms and soles begins in childhood and may be the major complaint of affected individuals in adult life. Nail dystrophy and milia are common. Both hyper- and hypopigmentation can occur. Mucosal involvement in EBS-gen sev may interfere with feeding, especially in neonates and infants. Blistering can be severe enough to result in neonatal or infant death.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:52520369
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
HPS3
Variant:
c.970+7A>G
rsID: rs114029765
Ref Allele: A
Alt Allele: G
Freq: 2.3955%uncommon
CADD: 0.097
ClinVar Submissions (4)
Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1.
Last Evaluated: Dec 16, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:149141387
Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1.
Last Evaluated: Dec 16, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:149141387
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 16, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:149141387
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
CANT1
Variant:
c.*829G>A
rsID: rs115856545
Ref Allele: C
Alt Allele: T
Freq: 2.4122%uncommon
CADD: 1.131
ClinVar Submissions (1)
A rare osteochondrodysplasia characterized by short stature, joint laxity, multiple dislocations, vertebral and metaphyseal abnormalities, and advanced carpotarsal ossification. Two forms have been identified: type 1 caused by mutation in the gene CANT1 and type 2 caused by mutations in the gene XYLT1.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:78992721
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
NFKBIA
Variant:
c.*421G>A
rsID: rs2273650
Ref Allele: C
Alt Allele: T
Freq: 2.4314%uncommon
CADD: 16.46
ClinVar Submissions (1)
EDAID2 is characterized by variable features of ectodermal dysplasia (e.g., hypo/anhidrosis, sparse hair, tooth anomalies) and various immunologic and infectious phenotypes of differing severity (summary by Boisson et al., 2017). Mutations in the NFKBIA gene result in functional impairment of NFKB (see 164011), a master transcription factor required for normal activation of immune responses. Interruption of NFKB signaling results in decreased production of proinflammatory cytokines and certain interferons, rendering patients susceptible to infection (McDonald et al., 2007). For discussion of genetic heterogeneity of ectodermal dysplasia and immune deficiency, see 300291.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 14:35401592
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
TMEM67
Variant:
c.2892A>C
(p.Thr964=)
rsID: rs16916221
Ref Allele: A
Alt Allele: C
Freq: 2.4712%uncommon
CADD: 3.469
ClinVar Submissions (5)
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Last Evaluated: Aug 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:93815432
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Last Evaluated: Aug 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:93815432
A rare, lethal, autosomal recessive inherited syndrome characterized by pulmonary hypoplasia, central nervous system malformations, and hepatic malformations.
Last Evaluated: Aug 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:93815432
A rare, lethal, autosomal recessive inherited syndrome characterized by pulmonary hypoplasia, central nervous system malformations, and hepatic malformations.
Last Evaluated: Aug 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:93815432
The nephronophthisis (NPH) phenotype is characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before age 30 years. Three age-based clinical subtypes are recongnized: infantile, juvenile, and adolescent/adult. Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia and facial dysmorphisms) or postnatally with renal manifestations that progress to ESRD before age 3 years. Juvenile NPH, the most prevalent subtype, typically presents with polydipsia and polyuria, growth retardation, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD). Hypertension is typically absent due to salt wasting. ESRD develops at a median age of 13 years. Ultrasound findings are increased echogenicity, reduced corticomedullary differentiation, and renal cysts (in 50% of affected individuals). Histologic findings include tubulointerstitial fibrosis, thickened and disrupted tubular basement membrane, sporadic corticomedullary cysts, and normal or reduced kidney size. Adolescent/ adult NPH is clinically similar to juvenile NPH, but ESRD develops at a median age of 19 years. Within a subtype inter- and intrafamilial variability in rate of progression to ESRD is considerable. Approximately 80%-90% of individuals with the NPH phenotype have no extrarenal features (i.e., they have isolated NPH); ~10%-20% have extrarenal manifestations that constitute a recognizable syndrome (e.g., Joubert syndrome, Bardet-Biedl syndrome, Jeune syndrome and related skeletal disorders, Meckel-Gruber syndrome, Senior-Løken syndrome, Leber congenital amaurosis, COACH syndrome, and oculomotor apraxia, Cogan type).
Last Evaluated: Aug 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:93815432
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:93815432
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
ANK3
Variant:
c.1491+6C>T
rsID: rs76733192
Ref Allele: G
Alt Allele: A
Freq: 2.4783%uncommon
CADD: 1.486
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 10:60200123
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
TRPM1
Variant:
c.1506+14A>G
rsID: rs17228080
Ref Allele: T
Alt Allele: C
Freq: 2.4879%uncommon
CADD: 2.19
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 15:31049361
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
RHPN2
Variant:
c.1552C>T
(p.Arg518Cys)
rsID: rs79314177
Ref Allele: G
Alt Allele: A
Freq: 2.4911%uncommon
CADD: 22.9
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 29, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:32991915
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
CASP10
Variant:
c.1337A>G
(p.Tyr446Cys)
rsID: rs17860405
Ref Allele: A
Alt Allele: G
Freq: 2.5086%uncommon
CADD: 5.646
ClinVar Submissions (3)
Autoimmune lymphoproliferative syndrome (ALPS), caused by defective lymphocyte homeostasis, is characterized by the following: Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age. Autoimmune disease, mostly directed toward blood cells. Lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma. In ALPS-FAS (the most common and best-characterized type of ALPS, associated with heterozygous germline pathogenic variants in FAS), non-malignant lymphoproliferation typically manifests in the first years of life, inexplicably waxes and wanes, and then often decreases without treatment in the second decade of life; in many affected individuals, however, neither splenomegaly nor the overall expansion of lymphocyte subsets in peripheral blood decreases. Although autoimmunity is often not present at the time of diagnosis or at the time of the most extensive lymphoproliferation, autoantibodies can be detected before autoimmune disease manifests clinically. In ALPS-FAS caused by homozygous or compound heterozygous (biallelic) pathogenic variants in FAS, severe lymphoproliferation occurs before, at, or shortly after birth, and usually results in death at an early age. ALPS-sFAS, resulting from somatic FAS pathogenic variants in selected cell populations, notably the alpha/beta double-negative T cells (a/ß-DNT cells), appears to be similar to ALPS-FAS resulting from heterozygous germline pathogenic variants in FAS, although lower incidence of splenectomy and lower lymphocyte counts have been reported in ALPS-sFAS and no cases of lymphoma have yet been published.
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:201209484
A rare, primary immunodeficiency with an autosomal dominant pattern of inheritance but incomplete penetrance. It is caused by a mutation in the CASP10 (caspase-10) gene that leads to defective Fas-induced apoptosis. Disruption of Fas-induced apoptosis impairs lymphocyte homeostasis and immune tolerance. Characteristic laboratory findings include an increase in circulating, double-negative (CD4-/CD8-) T cells in the setting of immune-mediated anemia, thrombocytopenia and neutropenia. Clinical signs present in childhood include fatigue, pallor, bruising, hepatosplenomegaly and chronic, non-malignant, non-infectious lymphadenopathy. The clinical course is influenced by a strong association with other autoimmune disorders and an increased risk for developing Hodgkin and non-Hodgkin lymphoma.
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:201209484
Autoimmune lymphoproliferative syndrome (ALPS), caused by defective lymphocyte homeostasis, is characterized by the following: Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age. Autoimmune disease, mostly directed toward blood cells. Lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma. In ALPS-FAS (the most common and best-characterized type of ALPS, associated with heterozygous germline pathogenic variants in FAS), non-malignant lymphoproliferation typically manifests in the first years of life, inexplicably waxes and wanes, and then often decreases without treatment in the second decade of life; in many affected individuals, however, neither splenomegaly nor the overall expansion of lymphocyte subsets in peripheral blood decreases. Although autoimmunity is often not present at the time of diagnosis or at the time of the most extensive lymphoproliferation, autoantibodies can be detected before autoimmune disease manifests clinically. In ALPS-FAS caused by homozygous or compound heterozygous (biallelic) pathogenic variants in FAS, severe lymphoproliferation occurs before, at, or shortly after birth, and usually results in death at an early age. ALPS-sFAS, resulting from somatic FAS pathogenic variants in selected cell populations, notably the alpha/beta double-negative T cells (a/ß-DNT cells), appears to be similar to ALPS-FAS resulting from heterozygous germline pathogenic variants in FAS, although lower incidence of splenectomy and lower lymphocyte counts have been reported in ALPS-sFAS and no cases of lymphoma have yet been published.
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:201209484
Autoimmune lymphoproliferative syndrome (ALPS), caused by defective lymphocyte homeostasis, is characterized by the following: Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age. Autoimmune disease, mostly directed toward blood cells. Lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma. In ALPS-FAS (the most common and best-characterized type of ALPS, associated with heterozygous germline pathogenic variants in FAS), non-malignant lymphoproliferation typically manifests in the first years of life, inexplicably waxes and wanes, and then often decreases without treatment in the second decade of life; in many affected individuals, however, neither splenomegaly nor the overall expansion of lymphocyte subsets in peripheral blood decreases. Although autoimmunity is often not present at the time of diagnosis or at the time of the most extensive lymphoproliferation, autoantibodies can be detected before autoimmune disease manifests clinically. In ALPS-FAS caused by homozygous or compound heterozygous (biallelic) pathogenic variants in FAS, severe lymphoproliferation occurs before, at, or shortly after birth, and usually results in death at an early age. ALPS-sFAS, resulting from somatic FAS pathogenic variants in selected cell populations, notably the alpha/beta double-negative T cells (a/ß-DNT cells), appears to be similar to ALPS-FAS resulting from heterozygous germline pathogenic variants in FAS, although lower incidence of splenectomy and lower lymphocyte counts have been reported in ALPS-sFAS and no cases of lymphoma have yet been published.
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:201209484
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
MYLK
Variant:
c.4194C>T
(p.His1398=)
rsID: rs17298941
Ref Allele: G
Alt Allele: A
Freq: 2.511%uncommon
CADD: 5.023
ClinVar Submissions (7)
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123657220
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123657220
Familial thoracic aortic aneurysm and dissection (familial TAAD) involves problems with the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. Familial TAAD affects the upper part of the aorta, near the heart. This part of the aorta is called the thoracic aorta because it is located in the chest (thorax). Other vessels that carry blood from the heart to the rest of the body (arteries) can also be affected.In familial TAAD, the aorta can become weakened and stretched (aortic dilatation), which can lead to a bulge in the blood vessel wall (an aneurysm). Aortic dilatation may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection), allowing blood to flow abnormally between the layers. These aortic abnormalities are potentially life-threatening because they can decrease blood flow to other parts of the body such as the brain or other vital organs, or cause the aorta to break open (rupture).The occurrence and timing of these aortic abnormalities vary, even within the same affected family. They can begin in childhood or not occur until late in life. Aortic dilatation is generally the first feature of familial TAAD to develop, although in some affected individuals dissection occurs with little or no aortic dilatation.Aortic aneurysms usually have no symptoms. However, depending on the size, growth rate, and location of these abnormalities, they can cause pain in the jaw, neck, chest, or back; swelling in the arms, neck, or head; difficult or painful swallowing; hoarseness; shortness of breath; wheezing; a chronic cough; or coughing up blood. Aortic dissections usually cause severe, sudden chest or back pain, and may also result in unusually pale skin (pallor), a very faint pulse, numbness or tingling (paresthesias) in one or more limbs, or paralysis.Familial TAAD may not be associated with other signs and symptoms. However, some individuals in affected families show mild features of related conditions called Marfan syndrome or Loeys-Dietz syndrome. These features include tall stature, stretch marks on the skin, an unusually large range of joint movement (joint hypermobility), and either a sunken or protruding chest. Occasionally, people with familial TAAD develop aneurysms in the brain or in the section of the aorta located in the abdomen (abdominal aorta). Some people with familial TAAD have heart abnormalities that are present from birth (congenital). Affected individuals may also have a soft out-pouching in the lower abdomen (inguinal hernia), an abnormal curvature of the spine (scoliosis), or a purplish skin discoloration (livedo reticularis) caused by abnormalities in the tiny blood vessels of the skin (dermal capillaries). However, these conditions are also common in the general population. Depending on the genetic cause of familial TAAD in particular families, they may have an increased risk of developing blockages in smaller arteries, which can lead to heart attack and stroke.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123657220
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123657220
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123657220
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
DYSF
Variant:
c.457+17G>C
rsID: rs115170960
Ref Allele: G
Alt Allele: C
Freq: 2.5221%uncommon
CADD: 0.116
ClinVar Submissions (3)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 10, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:71511938
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
AGL
Variant:
c.1160G>A
(p.Arg387Gln)
rsID: rs17121464
Ref Allele: G
Alt Allele: A
Freq: 2.5237%uncommon
CADD: 12.34
ClinVar Submissions (6)
Glycogen storage disease type III (GSD III) is characterized by variable liver, cardiac muscle, and skeletal muscle involvement. GSD IIIa is the most common subtype, present in about 85% of affected individuals; it manifests with liver and muscle involvement. GSD IIIb, with liver involvement only, comprises about 15% of all GSD III. In infancy and early childhood, liver involvement presents as ketotic hypoglycemia, hepatomegaly, hyperlipidemia, and elevated hepatic transaminases. In adolescence and adulthood, liver disease becomes less prominent. Hypertrophic cardiomyopathy develops in the majority of those with GSD IIIa, usually during childhood. Its clinical significance ranges from asymptomatic in the majority to severe cardiac dysfunction, congestive heart failure, and (rarely) sudden death. Skeletal myopathy manifesting as weakness is not usually evident in childhood, but slowly progresses, typically becoming prominent in the third to fourth decade.
Last Evaluated: Aug 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:99875231
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:99875231
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:99875231
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
ENPP1
Variant:
c.*3625G>A
rsID: rs150482147
Ref Allele: G
Alt Allele: A
Freq: 2.5261%uncommon
CADD: 1.52
ClinVar Submissions (1)
Generalized arterial calcification of infancy (GACI) is characterized by infantile onset of widespread arterial calcification and/or narrowing of large- and medium-sized vessels resulting in cardiovascular findings (which can include heart failure, respiratory distress, edema, cyanosis, hypertension, and/or cardiomegaly). Additional findings can include extravascular calcifications (particularly periarticular), typical skin and retinal manifestations of pseudoxanthoma elasticum (PXE), hearing loss, and development of rickets after infancy. While mortality in infancy is high, survival into the second and third decade has been reported.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:131894136
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:131894136
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
ATM
Variant:
c.*1427T>C
rsID: rs3092836
Ref Allele: T
Alt Allele: C
Freq: 2.5389%uncommon
CADD: 6.927
ClinVar Submissions (1)
Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Chromosomal breakage is a feature. AT cells are abnormally sensitive to killing by ionizing radiation (IR), and abnormally resistant to inhibition of DNA synthesis by ionizing radiation. The latter trait has been used to identify complementation groups for the classic form of the disease (Jaspers et al., 1988). At least 4 of these (A, C, D, and E) map to chromosome 11q23 (Sanal et al., 1990) and are associated with mutations in the ATM gene.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:108366935
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
BTD
Variant:
c.1336G>C
(p.Asp446His)
rsID: rs13078881
Ref Allele: G
Alt Allele: C
Freq: 2.5667%uncommon
CADD: 23.3
ClinVar Submissions (15)
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
This individual has one copy of the genetic mutation, and because it's autosomal recessive, they are likely a carrier rather than manifesting the condition. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Low clinical importance, pathogenic — This variant is implicated in partial and profound biotinidase deficiency. Alone, this variant is estimated to have a 52% loss of enzymatic activity. This variant is often found with A171T, and together they are reported to cause profound deficiency. Notably there is a report of asymptomatic double-mutant adults, so symptoms may have variable penetrance. This variant is found compound heterozygously with more serious mutations in cases of partial biotinidase deficiency.
Expert Reviewed Clinically Significant Conflicting/Uncertain
Hetero
Gene:
SLC22A12
Variant:
c.246C>T
(p.Asn82=)
rsID: rs3825017
Ref Allele: C
Alt Allele: T
Freq: 2.5667%uncommon
CADD: 1.132
ClinVar Submissions (1)
Renal hypouricemia is characterized by impaired uric acid reabsorption at the apical membrane of proximal renal tubule cells. The syndrome is not lethal and may be asymptomatic. However, it is accompanied by nephrolithiasis and exercise-induced acute renal failure in about 10% of patients (Ichida et al., 2008). Genetic Heterogeneity of Renal Hypouricemia See also RHUC2 (612076), which is caused by mutation in the SLC2A9 gene (606142).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:64591802
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
EGF
Variant:
c.1725-12C>A
rsID: rs11568990
Ref Allele: C
Alt Allele: A
Freq: 2.5691%uncommon
CADD: 0.037
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:109974691
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
AGRN
Variant:
c.2555A>G
(p.Gln852Arg)
rsID: rs9697293
Ref Allele: A
Alt Allele: G
Freq: 2.5739%uncommon
CADD: 4.231
ClinVar Submissions (3)
Congenital myasthenic syndromes (designated as CMS throughout this entry) are characterized by fatigable weakness of skeletal muscle (e.g., ocular, bulbar, limb muscles) with onset at or shortly after birth or in early childhood; rarely, symptoms may not manifest until later in childhood. Cardiac and smooth muscle are usually not involved. Severity and course of disease are highly variable, ranging from minor symptoms to progressive disabling weakness. In some subtypes of CMS, myasthenic symptoms may be mild, but sudden severe exacerbations of weakness or even sudden episodes of respiratory insufficiency may be precipitated by fever, infections, or excitement. Major findings of the neonatal-onset subtype include: respiratory insufficiency with sudden apnea and cyanosis; feeding difficulties; poor suck and cry; choking spells; eyelid ptosis; and facial, bulbar, and generalized weakness. Arthrogryposis multiplex congenita may also be present. Stridor in infancy may be an important clue to CMS. Later childhood-onset subtypes show abnormal muscle fatigability with difficulty in activities such as running or climbing stairs; motor milestones may be delayed; fluctuating eyelid ptosis and fixed or fluctuating extraocular muscle weakness are common presentations.
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:1045751
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:1045751
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
BBS4
Variant:
c.1249-35G>C
rsID: rs117852179
Ref Allele: G
Alt Allele: C
Freq: 2.5906%uncommon
CADD: 1.609
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 15:72736727
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
COL11A1
Variant:
c.1944+11T>C
rsID: rs71664954
Ref Allele: A
Alt Allele: G
Freq: 2.6312%uncommon
CADD: 7.663
ClinVar Submissions (4)
Fibrochondrogenesis is a severe, autosomal recessive, short-limbed skeletal dysplasia clinically characterized by a flat midface with a small nose and anteverted nares, significant shortening of all limb segments but relatively normal hands and feet, and a small bell-shaped thorax with a protuberant abdomen. Radiographically, the long bones are short and have broad metaphyseal ends, giving them a dumb-bell shape. The vertebral bodies are flat and, on lateral view, have a distinctive pinched appearance, with a hypoplastic posterior end and a rounded anterior end. The ribs are typically short and wide and have metaphyseal cupping at both ends (summary by Tompson et al., 2010). Genetic Heterogeneity of Fibrochondrogenesis Fibrochondrogenesis-2 (FBCG2; 614524) is caused by mutation in the COL11A2 gene (120290) on chromosome 6p21.3.
Last Evaluated: Oct 05, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:103004433
Stickler syndrome is a group of hereditary conditions characterized by a distinctive facial appearance, eye abnormalities, hearing loss, and joint problems. These signs and symptoms vary widely among affected individuals.A characteristic feature of Stickler syndrome is a somewhat flattened facial appearance. This appearance results from underdeveloped bones in the middle of the face, including the cheekbones and the bridge of the nose. A particular group of physical features called Pierre Robin sequence is also common in people with Stickler syndrome. Pierre Robin sequence includes an opening in the roof of the mouth (a cleft palate), a tongue that is placed further back than normal (glossoptosis), and a small lower jaw (micrognathia). This combination of features can lead to feeding problems and difficulty breathing.Many people with Stickler syndrome have severe nearsightedness (high myopia). In some cases, the clear gel that fills the eyeball (the vitreous) has an abnormal appearance, which is noticeable during an eye examination. Other eye problems are also common, including increased pressure within the eye (glaucoma), clouding of the lens of the eyes (cataracts), and tearing of the lining of the eye (retinal detachment). These eye abnormalities cause impaired vision or blindness in some cases.In people with Stickler syndrome, hearing loss varies in degree and may become more severe over time. The hearing loss may be sensorineural, meaning that it results from changes in the inner ear, or conductive, meaning that it is caused by abnormalities of the middle ear.Most people with Stickler syndrome have skeletal abnormalities that affect the joints. The joints of affected children and young adults may be loose and very flexible (hypermobile), though joints become less flexible with age. Arthritis often appears early in life and may cause joint pain or stiffness. Problems with the bones of the spine (vertebrae) can also occur, including abnormal curvature of the spine (scoliosis or kyphosis) and flattened vertebrae (platyspondyly). These spinal abnormalities may cause back pain.Researchers have described several types of Stickler syndrome, which are distinguished by their genetic causes and their patterns of signs and symptoms. In particular, the eye abnormalities and severity of hearing loss differ among the types. Type I has the highest risk of retinal detachment. Type II also includes eye abnormalities, but type III does not (and is often called non-ocular Stickler syndrome). Types II and III are more likely than type I to have significant hearing loss. Types IV, V, and VI are very rare and have each been diagnosed in only a few individuals.A condition similar to Stickler syndrome, called Marshall syndrome, is characterized by a distinctive facial appearance, eye abnormalities, hearing loss, and early-onset arthritis. Marshall syndrome can also include short stature. Some researchers have classified Marshall syndrome as a variant of Stickler syndrome, while others consider it to be a separate disorder.
Last Evaluated: Oct 05, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:103004433
Last Evaluated: Oct 05, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:103004433
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 05, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:103004433
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
ANO5
Variant:
c.2521-13A>G
rsID: rs76850415
Ref Allele: A
Alt Allele: G
Freq: 2.6328%uncommon
CADD: 5.143
ClinVar Submissions (3)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 12, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:22279531
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
ATM
Variant:
c.8786+8A>C
rsID: rs4986839
Ref Allele: A
Alt Allele: C
Freq: 2.6328%uncommon
CADD: 5.249
ClinVar Submissions (11)
Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Chromosomal breakage is a feature. AT cells are abnormally sensitive to killing by ionizing radiation (IR), and abnormally resistant to inhibition of DNA synthesis by ionizing radiation. The latter trait has been used to identify complementation groups for the classic form of the disease (Jaspers et al., 1988). At least 4 of these (A, C, D, and E) map to chromosome 11q23 (Sanal et al., 1990) and are associated with mutations in the ATM gene.
Last Evaluated: Feb 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 11
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:108353888
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Feb 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 11
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:108353888
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 11
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:108353888
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 11
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:108353888
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
DYSF
Variant:
c.570T>C
(p.Pro190=)
rsID: rs35392229
Ref Allele: T
Alt Allele: C
Freq: 2.648%uncommon
CADD: 5.977
ClinVar Submissions (6)
Dysferlinopathy includes a spectrum of muscle disease characterized by two main phenotypes: Miyoshi myopathy with primarily distal weakness and limb-girdle muscular dystrophy type 2B (LGMD2B) with primarily proximal weakness. Miyoshi myopathy (median age of onset 19 years) is characterized by muscle weakness and atrophy, most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles. The forearms may become mildly atrophic with decrease in grip strength; the small muscles of the hands are spared. LGMD2B is characterized by early weakness and atrophy of the pelvic and shoulder girdle muscles in adolescence or young adulthood, with slow progression. Other phenotypes are scapuloperoneal syndrome, distal myopathy with anterior tibial onset, elevated serum CK concentration only, and congenital muscular dystrophy.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:71513828
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:71513828
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:71513828
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:71513828
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
OTOA
Variant:
c.2382G>A
(p.Gln794=)
rsID: rs143890524
Ref Allele: G
Alt Allele: A
Freq: 2.6496%uncommon
CADD: 1.011
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 16, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:21736341
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
NDE1
Variant:
c.837C>T
(p.Tyr279=)
rsID: rs17283846
Ref Allele: C
Alt Allele: T
Freq: 2.6743%uncommon
CADD: 7.614
ClinVar Submissions (3)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:15696750
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:15696750
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
DYSF
Variant:
c.855+39T>C
rsID: rs74384941
Ref Allele: T
Alt Allele: C
Freq: 2.7037%uncommon
CADD: 2.363
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:71516281
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
KIF7
Variant:
c.2043T>A
(p.Val681=)
rsID: rs72750755
Ref Allele: A
Alt Allele: T
Freq: 2.7045%uncommon
CADD: 1.26
ClinVar Submissions (5)
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 15:89645161
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 15:89645161
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
IVD
Variant:
c.*447C>G
rsID: rs79191320
Ref Allele: C
Alt Allele: G
Freq: 2.7228%uncommon
CADD: 1.584
ClinVar Submissions (1)
Isovaleric acidemia is an inborn error of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase. It can present with severe neonatal ketoacidosis leading to death, but in milder cases recurrent episodes of ketoacidosis of varying degree occur later in infancy and childhood (summary by Vockley et al., 1991).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 15:40418710
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
IVD
Variant:
c.*596G>A
rsID: rs115034694
Ref Allele: G
Alt Allele: A
Freq: 2.7244%uncommon
CADD: 0.105
ClinVar Submissions (1)
Isovaleric acidemia is an inborn error of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase. It can present with severe neonatal ketoacidosis leading to death, but in milder cases recurrent episodes of ketoacidosis of varying degree occur later in infancy and childhood (summary by Vockley et al., 1991).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 15:40418859
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
IVD
Variant:
c.*195C>T
rsID: rs77680513
Ref Allele: C
Alt Allele: T
Freq: 2.7268%uncommon
CADD: 1.599
ClinVar Submissions (1)
Isovaleric acidemia is an inborn error of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase. It can present with severe neonatal ketoacidosis leading to death, but in milder cases recurrent episodes of ketoacidosis of varying degree occur later in infancy and childhood (summary by Vockley et al., 1991).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 15:40418458
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
MPL
Variant:
c.*662C>T
rsID: rs1763698
Ref Allele: C
Alt Allele: T
Freq: 2.7531%uncommon
CADD: 0.671
ClinVar Submissions (1)
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare disorder expressed in infancy and characterized by isolated thrombocytopenia and megakaryocytopenia with no physical anomalies (Muraoka et al., 1997). King et al. (2005) proposed a new classification of CAMT based on the course and outcome of the disease, as exemplified by 20 patients: CAMT type I (11 patients) was characterized by early onset of severe pancytopenia, decreased bone marrow activity, and very low platelet counts. CAMT type II (9 patients) was somewhat milder and characterized by transient increases of platelet counts up to nearly normal values during the first year of life and an onset of bone marrow failure at age 3 or later.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:43353434
Thrombocythemia, or thrombocytosis, is a myeloproliferative disorder characterized by excessive platelet production resulting in increased numbers of circulating platelets. Thrombocythemia can be associated with thrombotic or hemorrhagic episodes and occasional leukemic transformation (summary by Wiestner et al., 1998). Genetic Heterogeneity of Thrombocythemia THCYT2 (601977) is caused by germline or somatic mutation in the THPO receptor gene (MPL; 159530) on chromosome 1p34; THCYT3 (614521) is caused by germline or somatic mutation in the JAK2 gene (147796) on chromosome 9p; and a possible X-linked form (THCYTX; 300331) has been reported. Somatic mutations in the TET2 (612839), ASXL1 (612990), SH2B3 (605093), and SF3B1 (605590) genes have also been found in cases of essential thrombocythemia. Somatic mutation in the CALR gene (109091) occurs in approximately 70% of essential thrombocythemia patients who lack JAK2 and MPL mutations (Klampfl et al., 2013; Nangalia et al., 2013).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:43353434
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
SMAD9
Variant:
c.*2216G>A
rsID: rs117560648
Ref Allele: C
Alt Allele: T
Freq: 2.7754%uncommon
CADD: 0.569
ClinVar Submissions (1)
Pulmonary arterial hypertension (PAH) is characterized by widespread obstruction and obliteration of the smallest pulmonary arteries. When a sufficient number of vessels are occluded, the resistance to blood flow through the lungs increases, and the right ventricle attempts to compensate by generating higher pressure to maintain pulmonary blood flow. When the right ventricle can no longer compensate for the increased resistance, progressive heart failure ensues. Initial symptoms include dyspnea (60%), fatigue (19%), syncope (8%), chest pain (7%), palpitations (5%), and leg edema (3%). All ages are affected, but the mean age at diagnosis is 36 years. Mean survival after diagnosis is 2.8 years; current therapy does improve clinical function but has modest effect on survival. The term "heritable PAH" (HPAH) includes familial PAH (PAH that occurs in two or more family members) and simplex PAH (i.e., a single occurrence in a family) when a pathogenic variant has been identified. Most heritable PAH (75%) is caused by a pathogenic variant in BMPR2; pathogenic variants in other genes (i.e., ACVRL1, KCNK3, CAV1, SMAD9, BMPR1B) are considerably less common (1%-3%). HPAH has identical symptoms, signs, and histology as PAH of unknown cause. The time from onset of symptoms to diagnosis may be shorter in individuals with familial PAH, possibly because of familial awareness of the disease. Three retrospective studies suggest that persons with PAH who have a BMPR2 pathogenic variant exhibit more severe disease.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 13:36846460
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
RAB18
Variant:
c.*504A>G
rsID: rs12571836
Ref Allele: A
Alt Allele: G
Freq: 2.7961%uncommon
CADD: 4.776
ClinVar Submissions (1)
Warburg Micro syndrome is a rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism (summary by Morris-Rosendahl et al., 2010). Genetic Heterogeneity of Warburg Micro Syndrome Warburg Micro syndrome-2 (WARBM2; 614225) is caused by mutation in the RAB3GAP2 gene (609275) on chromosome 1q41. WARBM3 (614222) is caused by mutation in the RAB18 gene (602207) on chromosome 10p12. WARBM4 (615663) is caused by mutation in the TBC1D20 gene (611663) on chromosome 20p13. See also Martsolf syndrome (212720), a clinically overlapping but milder autosomal recessive disorder caused by autosomal recessive mutation in the RAB3GAP2 gene. Handley et al. (2013) provided an overview of the disease variants identified in the RAB3GAP1, RAB3GAP2, and RAB18 genes, noting that a total of 144 families with WARBM and 9 families with Martsolf syndrome had been studied. Mutations were identified in RAB3GAP1 in 41% of cases, in RAB3GAP2 in 7% of cases, and in RAB18 in 5% of cases. Although RAB18 had not been linked to RAB3 pathways, Handley et al. (2013) stated that mutations in all 3 genes cause an indistinguishable phenotype, making it likely that there is some functional overlap.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:27538555
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
RAB18
Variant:
c.*1542T>C
rsID: rs10508724
Ref Allele: T
Alt Allele: C
Freq: 2.7977%uncommon
CADD: 13.86
ClinVar Submissions (1)
Warburg Micro syndrome is a rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism (summary by Morris-Rosendahl et al., 2010). Genetic Heterogeneity of Warburg Micro Syndrome Warburg Micro syndrome-2 (WARBM2; 614225) is caused by mutation in the RAB3GAP2 gene (609275) on chromosome 1q41. WARBM3 (614222) is caused by mutation in the RAB18 gene (602207) on chromosome 10p12. WARBM4 (615663) is caused by mutation in the TBC1D20 gene (611663) on chromosome 20p13. See also Martsolf syndrome (212720), a clinically overlapping but milder autosomal recessive disorder caused by autosomal recessive mutation in the RAB3GAP2 gene. Handley et al. (2013) provided an overview of the disease variants identified in the RAB3GAP1, RAB3GAP2, and RAB18 genes, noting that a total of 144 families with WARBM and 9 families with Martsolf syndrome had been studied. Mutations were identified in RAB3GAP1 in 41% of cases, in RAB3GAP2 in 7% of cases, and in RAB18 in 5% of cases. Although RAB18 had not been linked to RAB3 pathways, Handley et al. (2013) stated that mutations in all 3 genes cause an indistinguishable phenotype, making it likely that there is some functional overlap.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:27539593
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
RAB18
Variant:
c.*3584C>T
rsID: rs11015862
Ref Allele: C
Alt Allele: T
Freq: 2.7993%uncommon
CADD: 1.416
ClinVar Submissions (1)
Warburg Micro syndrome is a rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism (summary by Morris-Rosendahl et al., 2010). Genetic Heterogeneity of Warburg Micro Syndrome Warburg Micro syndrome-2 (WARBM2; 614225) is caused by mutation in the RAB3GAP2 gene (609275) on chromosome 1q41. WARBM3 (614222) is caused by mutation in the RAB18 gene (602207) on chromosome 10p12. WARBM4 (615663) is caused by mutation in the TBC1D20 gene (611663) on chromosome 20p13. See also Martsolf syndrome (212720), a clinically overlapping but milder autosomal recessive disorder caused by autosomal recessive mutation in the RAB3GAP2 gene. Handley et al. (2013) provided an overview of the disease variants identified in the RAB3GAP1, RAB3GAP2, and RAB18 genes, noting that a total of 144 families with WARBM and 9 families with Martsolf syndrome had been studied. Mutations were identified in RAB3GAP1 in 41% of cases, in RAB3GAP2 in 7% of cases, and in RAB18 in 5% of cases. Although RAB18 had not been linked to RAB3 pathways, Handley et al. (2013) stated that mutations in all 3 genes cause an indistinguishable phenotype, making it likely that there is some functional overlap.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:27541635
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
DYSF
Variant:
c.1522+15C>G
rsID: rs76402294
Ref Allele: C
Alt Allele: G
Freq: 2.8136%uncommon
CADD: 2.892
ClinVar Submissions (4)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:71549406
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:71549406
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:71549406
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
SETX
Variant:
c.6936-27T>G
rsID: rs2296866
Ref Allele: A
Alt Allele: C
Freq: 2.82%uncommon
CADD: 6.261
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:132275447
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
RNASEH2B
Variant:
c.-210G>C
rsID: rs112702177
Ref Allele: G
Alt Allele: C
Freq: 2.8232%uncommon
CADD: 9.053
ClinVar Submissions (1)
Most characteristically, Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical disability. A subgroup of infants with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture highly suggestive of congenital infection. Otherwise, most affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. Typically, they demonstrate the subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. Over time, as many as 40% develop chilblain skin lesions on the fingers, toes, and ears. It is becoming apparent that atypical, sometimes milder, cases of AGS exist, and thus the true extent of the phenotype associated with pathogenic variants in the AGS-related genes is not yet known.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 13:50909867
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
CUBN
Variant:
c.7724C>G
(p.Pro2575Arg)
rsID: rs3740168
Ref Allele: G
Alt Allele: C
Freq: 2.8455%uncommon
CADD: 11.58
ClinVar Submissions (2)
A disorder characterized by the presence of ANEMIA, abnormally large red blood cells (megalocytes or macrocytes), and MEGALOBLASTS.
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:16906391
Type I MGCA is a rare autosomal recessive disorder of leucine catabolism. The metabolic landmark is urinary excretion of 3-methylglutaconic acid (3-MGA) and its derivatives 3-methylglutaric acid (3-MG) and 3-hydroxyisovaleric acid (3-HIVA). Two main presentations have been described: 1 with onset in childhood associated with the nonspecific finding of psychomotor retardation, and the other with onset in adulthood of a progressive neurodegenerative disorder characterized by ataxia, spasticity, and sometimes dementia; these patients develop white matter lesions in the brain. However, some asymptomatic pediatric patients have been identified by newborn screening and show no developmental abnormalities when reexamined later in childhood (summary by Wortmann et al., 2010). Genetic Heterogeneity and Classification of Methylglutaconic Aciduria Methylglutaconic aciduria is a clinically and genetically heterogeneous disorder. Type II MGCA (MGCA2), also known as Barth syndrome (BTHS; 302060), is caused by mutation in the tafazzin gene (TAZ; 300394) on chromosome Xq28. It is characterized by mitochondrial cardiomyopathy, short stature, skeletal myopathy, and recurrent infections; cognitive development is normal. Type III MGCA (MGCA3; 258501), caused by mutation in the OPA3 gene (606580) on chromosome 19q13, involves optic atrophy, movement disorder, and spastic paraplegia. In types II and III, the elevations of 3-methylglutaconate and 3-methylglutarate in urine are modest. Type IV MGCA (MGCA4; 250951) represents an unclassified group of patients who have severe psychomotor retardation and cerebellar dysgenesis. Type V MGCA (MGCA5; 610198), caused by mutation in the DNAJC19 gene (608977) on chromosome 3q26, is characterized by early-onset dilated cardiomyopathy with conduction defects, nonprogressive cerebellar ataxia, testicular dysgenesis, and growth failure in addition to 3-methylglutaconic aciduria (Chitayat et al., 1992; Davey et al., 2006). Type VI MGCA (MGCA6; 614739), caused by mutation in the SERAC1 gene (614725) on chromosome 6q25, includes deafness, encephalopathy, and a Leigh-like syndrome. Type VII MGCA (MGCA7; 616271), caused by mutation in the CLPB gene (616254) on chromosome 11q13, includes cataracts, neurologic involvement, and neutropenia. Type VIII MCGA (MGCA8; 617248) is caused by mutation in the HTRA2 gene (606441) on chromosome 2p13. Type IX MCGA (MGCA9; 617698) is caused by mutation in the TIMM50 gene (607381) on chromosome 19q13. Eriguchi et al. (2006) noted that type I MGCA is very rare, with only 13 patients reported in the literature as of 2003. Wortmann et al. (2013) proposed a pathomechanism-based classification for 'inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature.'
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:16906391
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
FANCE
Variant:
c.1071C>T
(p.Leu357=)
rsID: rs3823434
Ref Allele: C
Alt Allele: T
Freq: 2.8622%uncommon
CADD: 8.313
ClinVar Submissions (3)
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract – are more common in individuals with FA.
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:35458398
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract – are more common in individuals with FA.
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:35458398
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:35458398
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
TBK1
Variant:
c.66T>C
(p.Asn22=)
rsID: rs41292019
Ref Allele: T
Alt Allele: C
Freq: 2.8726%uncommon
CADD: 21.9
ClinVar Submissions (2)
Frontotemporal dementia and/or amyotrophic lateral sclerosis-4 is an autosomal dominant neurodegenerative disorder characterized by adult or late adult onset of cognitive impairment, behavioral abnormalities, and speech apraxia and/or upper and lower motor neuron signs. The phenotype is highly variable (summary by Freischmidt et al., 2015). For a discussion of genetic heterogeneity of FTDALS, see FTDALS1 (105550).
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:64455936
Glaucomas are a group of common neurodegenerative diseases of the optic nerve and retinal ganglion cells, characterized by progressive cupping of the optic nerve head with resultant visual field loss. Elevated intraocular pressure (IOP) is a strong risk factor for glaucoma; however, glaucoma can occur at any IOP. The most common form of glaucoma in the US is primary open-angle glaucoma (POAG; see 137760). POAG that occurs with an IOP below an arbitrary threshold of 21 mm Hg is often termed 'normal tension glaucoma' (summary by Fingert et al., 2011). For a discussion of genetic heterogeneity of primary open angle glaucoma, see 137760.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:64455936
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
SLC25A15
Variant:
c.*48T>A
rsID: rs145530626
Ref Allele: T
Alt Allele: A
Freq: 2.8797%uncommon
CADD: 15.86
ClinVar Submissions (1)
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is characterized by variable clinical presentation and age of onset. Neonatal onset (~12% of affected individuals). Infants are normal for the first 24-48 hours followed by onset of symptoms related to hyperammonemia (poor feeding, vomiting, lethargy, low temperature, rapid breathing). Information on long-term outcome is limited. Infancy, childhood, and adult presentation (~88%). Affected individuals may present with: Chronic neurocognitive deficits (including developmental delay, ataxia, spasticity, learning disabilities, cognitive deficits and/or unexplained seizures); Acute encephalopathy secondary to hyperammonemic crisis precipitated by a variety of factors; and Chronic liver dysfunction (unexplained elevation of liver transaminases with or without mild coagulopathy, with or without mild hyperammonemia and protein intolerance). Neurologic findings and cognitive abilities can continue to deteriorate despite early metabolic control that prevents hyperammonemia.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 13:40809715
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
BRAT1
Variant:
c.854G>A
(p.Arg285Gln)
rsID: rs77213198
Ref Allele: C
Alt Allele: T
Freq: 2.8813%uncommon
CADD: 0.496
ClinVar Submissions (2)
Lethal neonatal rigidity and multifocal seizure syndrome is a severe autosomal recessive epileptic encephalopathy characterized by onset of rigidity and intractable seizures at or soon after birth. Affected infants achieve no developmental milestones and die within the first months or years of life (summary by Saitsu et al., 2014).
Last Evaluated: Sep 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:2543273
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Sep 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:2543273
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
IL36RN
Variant:
c.*935G>C
rsID: rs11675540
Ref Allele: G
Alt Allele: C
Freq: 2.8917%uncommon
CADD: 6.278
ClinVar Submissions (1)
Generalized pustular psoriasis (GPP) is a life-threatening disease characterized by sudden, repeated episodes of high-grade fever, generalized rash, and disseminated pustules, with hyperleukocytosis and elevated serum levels of C-reactive protein (123260) (summary by Marrakchi et al., 2011). GPP often presents in patients with existing or prior psoriasis vulgaris (PV; see 177900); however, GPP can develop without a history of PV (Sugiura et al., 2013). Palmoplantar pustulosis and acrodermatitis continua of Hallopeau represent acral forms of pustular psoriasis that have historically been grouped with GPP (summary by Setta-Kaffetzi et al., 2013). GPP in association with sterile multifocal osteomyelitis and periostitis (612852) is caused by mutation in the IL1RN gene (147679). Capon (2013) noted that the percentage of GPP patients reported to be negative for mutation in IL36RN ranges from 51 to 84%, indicative of genetic heterogeneity in the generalized pustular form of psoriasis. For a discussion of genetic heterogeneity of psoriasis, see PSORS1 (177900).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:113063612
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
CHD7
Variant:
c.6135G>A
(p.Pro2045=)
rsID: rs6999971
Ref Allele: G
Alt Allele: A
Freq: 2.9187%uncommon
CADD: 3.361
ClinVar Submissions (8)
CHARGE is a mnemonic for coloboma, heart defects, choanal atresia, retarded growth and development, genital abnormalities, and ear anomalies. CHARGE syndrome is characterized by the following: Unilateral or bilateral coloboma of the iris, retina-choroid, and/or disc with or without microphthalmos (80%-90% of individuals). Unilateral or bilateral choanal atresia or stenosis (50%-60%). Cranial nerve dysfunction resulting in hyposmia or anosmia, unilateral or bilateral facial palsy (40%), impaired hearing, and/or swallowing problems (70%-90%). Abnormal outer ears, ossicular malformations, Mondini defect of the cochlea and absent or hypoplastic semicircular canals (>90%). Cryptorchidism in males and hypogonadotropic hypogonadism in both males and females. Developmental delay. Cardiovascular malformations (75%-85%). Growth deficiency (70%-80%). Orofacial clefts (15%-20%). Tracheoesophageal fistula (15%-20%). Neonates with CHARGE syndrome often have multiple life-threatening medical conditions. Feeding difficulties are a major cause of morbidity in all age groups.
Last Evaluated: Mar 02, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:60852860
Last Evaluated: Mar 02, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:60852860
Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the presence of low circulating concentrations of sex steroids. IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome) in approximately 60%. IGD can first become apparent in infancy, adolescence, or adulthood. Infant boys with congenital IGD often have micropenis and cryptorchidism. Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination. Adult males with IGD tend to have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth, deepening of the voice), decreased muscle mass, diminished libido, erectile dysfunction, and infertility. Adult females have little or no breast development and primary amenorrhea. Although skeletal maturation is delayed, the rate of linear growth is usually normal except for the absence of a distinct pubertal growth spurt.
Last Evaluated: Mar 02, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:60852860
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Mar 02, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:60852860
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 02, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:60852860
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
DSC2
Variant:
c.2393G>A
(p.Arg798Gln)
rsID: rs61731921
Ref Allele: C
Alt Allele: T
Freq: 2.9219%uncommon
CADD: 0.75
ClinVar Submissions (10)
Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).
Last Evaluated: Aug 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 10
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 18:31069009
Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).
Last Evaluated: Aug 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 10
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 18:31069009
Last Evaluated: Aug 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 10
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 18:31069009
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 10
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 18:31069009
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
CASP10
Variant:
c.*815C>T
rsID: rs17860409
Ref Allele: C
Alt Allele: T
Freq: 2.9387%uncommon
CADD: 0.087
ClinVar Submissions (1)
Autoimmune lymphoproliferative syndrome (ALPS), caused by defective lymphocyte homeostasis, is characterized by the following: Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age. Autoimmune disease, mostly directed toward blood cells. Lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma. In ALPS-FAS (the most common and best-characterized type of ALPS, associated with heterozygous germline pathogenic variants in FAS), non-malignant lymphoproliferation typically manifests in the first years of life, inexplicably waxes and wanes, and then often decreases without treatment in the second decade of life; in many affected individuals, however, neither splenomegaly nor the overall expansion of lymphocyte subsets in peripheral blood decreases. Although autoimmunity is often not present at the time of diagnosis or at the time of the most extensive lymphoproliferation, autoantibodies can be detected before autoimmune disease manifests clinically. In ALPS-FAS caused by homozygous or compound heterozygous (biallelic) pathogenic variants in FAS, severe lymphoproliferation occurs before, at, or shortly after birth, and usually results in death at an early age. ALPS-sFAS, resulting from somatic FAS pathogenic variants in selected cell populations, notably the alpha/beta double-negative T cells (a/ß-DNT cells), appears to be similar to ALPS-FAS resulting from heterozygous germline pathogenic variants in FAS, although lower incidence of splenectomy and lower lymphocyte counts have been reported in ALPS-sFAS and no cases of lymphoma have yet been published.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:201218556
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
HPS3
Variant:
c.1479G>A
(p.Thr493=)
rsID: rs34197730
Ref Allele: G
Alt Allele: A
Freq: 2.9434%uncommon
CADD: 2.123
ClinVar Submissions (3)
Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:149155185
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:149155185
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
TMEM70
Variant:
c.*785G>A
rsID: rs66498650
Ref Allele: G
Alt Allele: A
Freq: 2.9474%uncommon
CADD: 13.85
ClinVar Submissions (1)
Mitochondrial complex V deficiency is a shortage (deficiency) of a protein complex called complex V or a loss of its function. Complex V is found in cell structures called mitochondria, which convert the energy from food into a form that cells can use. Complex V is the last of five mitochondrial complexes that carry out a multistep process called oxidative phosphorylation, through which cells derive much of their energy.Mitochondrial complex V deficiency can cause a wide variety of signs and symptoms affecting many organs and systems of the body, particularly the nervous system and the heart. The disorder can be life-threatening in infancy or early childhood. Affected individuals may have feeding problems, slow growth, low muscle tone (hypotonia), extreme fatigue (lethargy), and developmental delay. They tend to develop elevated levels of lactic acid in the blood (lactic acidosis), which can cause nausea, vomiting, weakness, and rapid breathing. High levels of ammonia in the blood (hyperammonemia) can also occur in affected individuals, and in some cases result in abnormal brain function (encephalopathy) and damage to other organs.Another common feature of mitochondrial complex V deficiency is hypertrophic cardiomyopathy. This condition is characterized by thickening (hypertrophy) of the heart (cardiac) muscle that can lead to heart failure. People with mitochondrial complex V deficiency may also have a characteristic pattern of facial features, including a high forehead, curved eyebrows, outside corners of the eyes that point downward (downslanting palpebral fissures), a prominent bridge of the nose, low-set ears, thin lips, and a small chin (micrognathia).Some people with mitochondrial complex V deficiency have groups of signs and symptoms that are classified as a specific syndrome. For example, mitochondrial complex V deficiency can cause a condition called neuropathy, ataxia, and retinitis pigmentosa (NARP). NARP causes a variety of signs and symptoms chiefly affecting the nervous system. Beginning in childhood or early adulthood, most people with NARP experience numbness, tingling, or pain in the arms and legs (sensory neuropathy); muscle weakness; and problems with balance and coordination (ataxia). Many affected individuals also have cognitive impairment and an eye disorder called retinitis pigmentosa that causes vision loss.A condition called Leigh syndrome can also be caused by mitochondrial complex V deficiency. Leigh syndrome is characterized by progressive loss of mental and movement abilities (developmental or psychomotor regression) and typically results in death within 2 to 3 years after the onset of symptoms. Both NARP and Leigh syndrome can also have other causes.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 8:73982406
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
GLI2
Variant:
c.*569T>A
rsID: rs75544832
Ref Allele: T
Alt Allele: A
Freq: 2.9554%uncommon
CADD: 9.083
ClinVar Submissions (1)
Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having "microform" HPE.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:120991244
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
NALCN
Variant:
c.2637-10T>G
rsID: rs16958350
Ref Allele: A
Alt Allele: C
Freq: 2.9697%uncommon
CADD: 22.6
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:101104660
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
EFHC1
Variant:
c.*2164G>A
rsID: rs59722297
Ref Allele: G
Alt Allele: A
Freq: 2.9761%uncommon
CADD: 7.252
ClinVar Submissions (1)
Juvenile myoclonic epilepsy is a subtype of idiopathic generalized epilepsy (EIG; see 600669) affecting up to 26% of all individuals with EIG. Individuals with JME have afebrile seizures only, with onset in adolescence of myoclonic jerks. Myoclonic jerks occur usually in the morning (Janz and Durner, 1997). Genetic Heterogeneity of Juvenile Myoclonic Seizures Susceptibility to EJM can be conferred by variation in several other genes: EJM5 (611136), by variation in the GABRA1 gene (137160) on 5q34; EJM6 (see 607682), by variation in the CACNB4 gene (601949) on 2q23; EJM7 (see 613060), by variation in the GABRD gene (137163) on 1p36; EJM8 (see 607628), by variation in the CLCN2 gene (600570) on 3q27; and EJM10 (617924), by variation in the ICK gene (612325) on chromosome 6p12. In addition, EJM loci have been identified by linkage analysis: EJM2 (see 604827) on 15q14, EJM3 (608816) on 6p21, EJM4 (611364) on 5q12-q14, and EJM9 (614280) on 2q33-q36.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:52494505
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
C2;CFB
Variant:
c.504G>A
(p.Pro168=)
rsID: rs4151669
Ref Allele: G
Alt Allele: A
Freq: 2.9904%uncommon
CADD: 1.142
ClinVar Submissions (1)
Hemolytic-uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia, and renal failure caused by platelet thrombi in the microcirculation of the kidney and other organs. The onset of atypical HUS (aHUS) ranges from the neonatal period to adulthood. Genetic aHUS accounts for an estimated 60% of all aHUS. Individuals with genetic aHUS frequently experience relapse even after complete recovery following the presenting episode; 60% of genetic aHUS progresses to end-stage renal disease (ESRD).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:31947367
Complement component 2 deficiency is a disorder that causes the immune system to malfunction, resulting in a form of immunodeficiency. Immunodeficiencies are conditions in which the immune system is not able to protect the body effectively from foreign invaders such as bacteria and viruses. People with complement component 2 deficiency have a significantly increased risk of recurrent bacterial infections, specifically of the lungs (pneumonia), the membrane covering the brain and spinal cord (meningitis), and the blood (sepsis), which may be life-threatening. These infections most commonly occur in infancy and childhood and become less frequent in adolescence and adulthood.Complement component 2 deficiency is also associated with an increased risk of developing autoimmune disorders such as systemic lupus erythematosus (SLE) or vasculitis. Autoimmune disorders occur when the immune system malfunctions and attacks the body's tissues and organs. Between 10 and 20 percent of individuals with complement component 2 deficiency develop SLE. Females with complement component 2 deficiency are more likely to have SLE than affected males, but this is also true of SLE in the general population.The severity of complement component 2 deficiency varies widely. While some affected individuals experience recurrent infections and other immune system difficulties, others do not have any health problems related to the disorder.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:31947367
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells of the macula lutea.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:31947367
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Homo
Gene:
ADGRV1
Variant:
c.16248C>T
(p.Val5416=)
rsID: rs3763073
Ref Allele: C
Alt Allele: T
Freq: 3.0063%uncommon
CADD: 0.003
ClinVar Submissions (4)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:90823476
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:90823476
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
NFU1
Variant:
c.62+80T>C
rsID: rs6758700
Ref Allele: A
Alt Allele: G
Freq: 3.0215%uncommon
CADD: 7.928
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 14, 2013
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:69437281
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
GLI3
Variant:
c.*265A>C
rsID: rs201493390
Ref Allele: T
Alt Allele: G
Freq: 3.0223%uncommon
CADD: 7.597
ClinVar Submissions (1)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 7:41964065
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 7:41964065
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 7:41964065
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
CFB
Variant:
c.*23C>T
rsID: rs4151672
Ref Allele: C
Alt Allele: T
Freq: 3.0294%uncommon
CADD: 2.138
ClinVar Submissions (1)
Hemolytic-uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia, and renal failure caused by platelet thrombi in the microcirculation of the kidney and other organs. The onset of atypical HUS (aHUS) ranges from the neonatal period to adulthood. Genetic aHUS accounts for an estimated 60% of all aHUS. Individuals with genetic aHUS frequently experience relapse even after complete recovery following the presenting episode; 60% of genetic aHUS progresses to end-stage renal disease (ESRD).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:31952053
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells of the macula lutea.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:31952053
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Homo
Gene:
C2
Variant:
c.954G>C
(p.Glu318Asp)
rsID: rs9332739
Ref Allele: G
Alt Allele: C
Freq: 3.0302%uncommon
CADD: 13.09
ClinVar Submissions (3)
Age-related macular degeneration is an eye disease that is a leading cause of vision loss in older people in developed countries. The vision loss usually becomes noticeable in a person's sixties or seventies and tends to worsen over time.Age-related macular degeneration mainly affects central vision, which is needed for detailed tasks such as reading, driving, and recognizing faces. The vision loss in this condition results from a gradual deterioration of light-sensing cells in the tissue at the back of the eye that detects light and color (the retina). Specifically, age-related macular degeneration affects a small area near the center of the retina, called the macula, which is responsible for central vision. Side (peripheral) vision and night vision are generally not affected, but reduced dim light (scotopic) vision often occurs in the early stages of the disease.Researchers have described two major types of age-related macular degeneration, known as the dry form and the wet form. The dry form is much more common, accounting for 85 to 90 percent of all cases of age-related macular degeneration. It is characterized by a buildup of yellowish deposits called drusen beneath the retina and vision loss that worsens slowly over time. The condition typically affects vision in both eyes, although vision loss often occurs in one eye before the other.The wet form of age-related macular degeneration is associated with severe vision loss that can worsen rapidly. This form of the condition is characterized by the growth of abnormal, fragile blood vessels underneath the macula. These vessels leak blood and fluid, which damages the macula and makes central vision appear blurry and distorted.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:31936027
OMIM Allelic Variant: 613927.0004
Complement component 2 deficiency is a disorder that causes the immune system to malfunction, resulting in a form of immunodeficiency. Immunodeficiencies are conditions in which the immune system is not able to protect the body effectively from foreign invaders such as bacteria and viruses. People with complement component 2 deficiency have a significantly increased risk of recurrent bacterial infections, specifically of the lungs (pneumonia), the membrane covering the brain and spinal cord (meningitis), and the blood (sepsis), which may be life-threatening. These infections most commonly occur in infancy and childhood and become less frequent in adolescence and adulthood.Complement component 2 deficiency is also associated with an increased risk of developing autoimmune disorders such as systemic lupus erythematosus (SLE) or vasculitis. Autoimmune disorders occur when the immune system malfunctions and attacks the body's tissues and organs. Between 10 and 20 percent of individuals with complement component 2 deficiency develop SLE. Females with complement component 2 deficiency are more likely to have SLE than affected males, but this is also true of SLE in the general population.The severity of complement component 2 deficiency varies widely. While some affected individuals experience recurrent infections and other immune system difficulties, others do not have any health problems related to the disorder.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:31936027
OMIM Allelic Variant: 613927.0004
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells of the macula lutea.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:31936027
OMIM Allelic Variant: 613927.0004
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:31936027
OMIM Allelic Variant: 613927.0004
The individual has two copies of the variant, which suggests they may manifest the associated condition or trait. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Clinically Significant Conflicting/Uncertain
Homo
Gene:
C2;CFB
Variant:
c.26T>A
(p.Leu9His)
rsID: rs4151667
Ref Allele: T
Alt Allele: A
Freq: 3.035%uncommon
CADD: 23.1
ClinVar Submissions (3)
Age-related macular degeneration is an eye disease that is a leading cause of vision loss in older people in developed countries. The vision loss usually becomes noticeable in a person's sixties or seventies and tends to worsen over time.Age-related macular degeneration mainly affects central vision, which is needed for detailed tasks such as reading, driving, and recognizing faces. The vision loss in this condition results from a gradual deterioration of light-sensing cells in the tissue at the back of the eye that detects light and color (the retina). Specifically, age-related macular degeneration affects a small area near the center of the retina, called the macula, which is responsible for central vision. Side (peripheral) vision and night vision are generally not affected, but reduced dim light (scotopic) vision often occurs in the early stages of the disease.Researchers have described two major types of age-related macular degeneration, known as the dry form and the wet form. The dry form is much more common, accounting for 85 to 90 percent of all cases of age-related macular degeneration. It is characterized by a buildup of yellowish deposits called drusen beneath the retina and vision loss that worsens slowly over time. The condition typically affects vision in both eyes, although vision loss often occurs in one eye before the other.The wet form of age-related macular degeneration is associated with severe vision loss that can worsen rapidly. This form of the condition is characterized by the growth of abnormal, fragile blood vessels underneath the macula. These vessels leak blood and fluid, which damages the macula and makes central vision appear blurry and distorted.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:31946247
OMIM Allelic Variant: 138470.0003
Hemolytic-uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia, and renal failure caused by platelet thrombi in the microcirculation of the kidney and other organs. The onset of atypical HUS (aHUS) ranges from the neonatal period to adulthood. Genetic aHUS accounts for an estimated 60% of all aHUS. Individuals with genetic aHUS frequently experience relapse even after complete recovery following the presenting episode; 60% of genetic aHUS progresses to end-stage renal disease (ESRD).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:31946247
OMIM Allelic Variant: 138470.0003
Complement component 2 deficiency is a disorder that causes the immune system to malfunction, resulting in a form of immunodeficiency. Immunodeficiencies are conditions in which the immune system is not able to protect the body effectively from foreign invaders such as bacteria and viruses. People with complement component 2 deficiency have a significantly increased risk of recurrent bacterial infections, specifically of the lungs (pneumonia), the membrane covering the brain and spinal cord (meningitis), and the blood (sepsis), which may be life-threatening. These infections most commonly occur in infancy and childhood and become less frequent in adolescence and adulthood.Complement component 2 deficiency is also associated with an increased risk of developing autoimmune disorders such as systemic lupus erythematosus (SLE) or vasculitis. Autoimmune disorders occur when the immune system malfunctions and attacks the body's tissues and organs. Between 10 and 20 percent of individuals with complement component 2 deficiency develop SLE. Females with complement component 2 deficiency are more likely to have SLE than affected males, but this is also true of SLE in the general population.The severity of complement component 2 deficiency varies widely. While some affected individuals experience recurrent infections and other immune system difficulties, others do not have any health problems related to the disorder.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:31946247
OMIM Allelic Variant: 138470.0003
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells of the macula lutea.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:31946247
OMIM Allelic Variant: 138470.0003
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:31946247
OMIM Allelic Variant: 138470.0003
The individual has two copies of the variant, which suggests they may manifest the associated condition or trait. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Low clinical importance, Uncertain protective — This variant typically occurs along with E318D, forming the H10 haplotype. This variant appears to be protective; it was associated with a significantly lower incidence of age-related macular degeneration in an American study (OR = 0.45).
Clinically Significant Conflicting/Uncertain
Homo
Gene:
PNPT1
Variant:
c.1074-15C>T
rsID: rs76693423
Ref Allele: G
Alt Allele: A
Freq: 3.039%uncommon
CADD: 3.841
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 12, 2013
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:55667108
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
IGLL1
Variant:
c.475G>A
(p.Gly159Ser)
rsID: rs139571703
Ref Allele: C
Alt Allele: T
Freq: 3.0414%uncommon
CADD: 19.81
ClinVar Submissions (1)
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 22:23573433
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
TUBB
Variant:
c.651G>A
(p.Leu217=)
rsID: rs25497
Ref Allele: G
Alt Allele: A
Freq: 3.0677%uncommon
CADD: 15.54
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 02, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:30723713
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
TMC8
Variant:
c.1665-5G>T
rsID: rs11651864
Ref Allele: G
Alt Allele: T
Freq: 3.0685%uncommon
CADD: 6.376
ClinVar Submissions (1)
Epidermodysplasia verruciformis (EV) is a rare genodermatosis associated with a high risk of skin cancer. EV results from an abnormal susceptibility to specific related human papillomavirus (HPV) genotypes and to the oncogenic potential of some of them, mainly HPV5. Infection with EV-associated HPV leads to the early development of disseminated flat wart-like and pityriasis versicolor-like lesions. Patients are unable to reject their lesions, and cutaneous Bowen carcinomas in situ and invasive squamous cell carcinomas develop in about half of them, mainly on sun-exposed areas (summary by Ramoz et al., 2000). Genetic Heterogeneity of Susceptibility to Epidermodysplasia Verruciformis Susceptibility to EV2 (618231) is conferred by mutation in the TMC8 gene (605829) on chromosome 17q25; EV3 (618267) by mutation in the CIB1 gene (602293) on chromosome 15q26; EV4 (618307) by mutation in the RHOH gene (602037) on chromosome 4p13; and EV5 (618309) by mutation in the IL7 gene (146660) on chromosome 8q12.
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:78138569
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
TMC8
Variant:
c.1501G>A
(p.Val501Ile)
rsID: rs11651675
Ref Allele: G
Alt Allele: A
Freq: 3.0931%uncommon
CADD: 3.957
ClinVar Submissions (1)
Epidermodysplasia verruciformis (EV) is a rare genodermatosis associated with a high risk of skin cancer. EV results from an abnormal susceptibility to specific related human papillomavirus (HPV) genotypes and to the oncogenic potential of some of them, mainly HPV5. Infection with EV-associated HPV leads to the early development of disseminated flat wart-like and pityriasis versicolor-like lesions. Patients are unable to reject their lesions, and cutaneous Bowen carcinomas in situ and invasive squamous cell carcinomas develop in about half of them, mainly on sun-exposed areas (summary by Ramoz et al., 2000). Genetic Heterogeneity of Susceptibility to Epidermodysplasia Verruciformis Susceptibility to EV2 (618231) is conferred by mutation in the TMC8 gene (605829) on chromosome 17q25; EV3 (618267) by mutation in the CIB1 gene (602293) on chromosome 15q26; EV4 (618307) by mutation in the RHOH gene (602037) on chromosome 4p13; and EV5 (618309) by mutation in the IL7 gene (146660) on chromosome 8q12.
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:78138156
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
PNPO
Variant:
c.*106A>T
rsID: rs117508783
Ref Allele: A
Alt Allele: T
Freq: 3.1242%uncommon
CADD: 4.828
ClinVar Submissions (1)
PNPOD is an autosomal recessive inborn error of metabolism resulting in vitamin B6 deficiency that manifests as neonatal-onset severe seizures and subsequent encephalopathy. Patients with PNPO mutations tend to respond better to treatment with pyridoxal 5-prime phosphate (PLP) than with pyridoxine (summary by Plecko et al., 2014).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:47946888
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Homo
Gene:
CYP21A2
Variant:
c.-4C>T
rsID: rs6470
Ref Allele: C
Alt Allele: T
Freq: 3.125%uncommon
CADD: 0.65
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:32038419
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Homo
Gene:
GJB4
Variant:
c.507C>G
(p.Cys169Trp)
rsID: rs79193415
Ref Allele: C
Alt Allele: G
Freq: 3.1481%uncommon
CADD: 25.8
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:34761761
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
SUMF1
Variant:
c.*471T>G
rsID: rs2259818
Ref Allele: A
Alt Allele: C
Freq: 3.1855%uncommon
CADD: 7.953
ClinVar Submissions (1)
Multiple sulfatase deficiency is an autosomal recessive inborn error of metabolism resulting in tissue accumulation of sulfatides, sulfated glycosaminoglycans, sphingolipids, and steroid sulfates. The enzymatic defect affects the whole family of sulfatase enzymes; thus, the disorder combines features of metachromatic leukodystrophy (250100) and of various mucopolysaccharidoses (see, e.g., MPS6; 253200). Affected individuals show neurologic deterioration with mental retardation, skeletal anomalies, organomegaly, and ichthyosis. Different types of MSD can be distinguished according to the age of onset: neonatal, late infantile (0 to 2 years), and juvenile (2 to 4 years). Neonatal MSD is the most severe form with a broad range of mucopolysaccharidosis-like symptoms and death within the first year of life. Late-infantile MSD, which includes the majority of cases, resembles late-infantile metachromatic leukodystrophy with progressive loss of mental and motor abilities and skeletal changes. There is also an attenuated form of late-infantile MSD with onset beyond the second year of life. Rare cases of juvenile-onset MSD have been reported with onset of symptoms in late childhood and slower progression (Blanco-Aguirre et al., 2001) (summary by Schlotawa et al., 2011).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:4361673
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
HPS1
Variant:
c.11T>C
(p.Val4Ala)
rsID: rs58548334
Ref Allele: A
Alt Allele: G
Freq: 3.1879%uncommon
CADD: 25.6
ClinVar Submissions (3)
Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:98443230
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:98443230
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
COL5A1
Variant:
c.2892C>T
(p.Gly964=)
rsID: rs78511105
Ref Allele: C
Alt Allele: T
Freq: 3.1887%uncommon
CADD: 6.172
ClinVar Submissions (7)
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:134796895
Classic Ehlers-Danlos syndrome (cEDS) is a connective tissue disorder characterized by skin hyperextensibility, atrophic scarring, and generalized joint hypermobility (GJH). The skin is soft and doughy to the touch, and hyperextensible, extending easily and snapping back after release (unlike lax, redundant skin, as in cutis laxa). The skin is fragile, as manifested by splitting of the dermis following relatively minor trauma, especially over pressure points (knees, elbows) and areas prone to trauma (shins, forehead, chin). Wound healing is poor, and stretching of scars after apparently successful primary wound healing is characteristic. Complications of joint hypermobility, such as dislocations of the shoulder, patella, digits, hip, radius, and clavicle, usually resolve spontaneously or are easily managed by the affected individual. Other features include hypotonia with delayed motor development, fatigue and muscle cramps, and easy bruising. Mitral valve prolapse can occur infrequently, but tends to be of little clinical consequence. Aortic root dilatation has been reported, appears to be more common in young individuals, and rarely progresses.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:134796895
Ehlers-Danlos syndrome is a group of disorders that affect connective tissues supporting the skin, bones, blood vessels, and many other organs and tissues. Defects in connective tissues cause the signs and symptoms of these conditions, which range from mildly loose joints to life-threatening complications.The various forms of Ehlers-Danlos syndrome have been classified in several different ways. Originally, 11 forms of Ehlers-Danlos syndrome were named using Roman numerals to indicate the types (type I, type II, and so on). In 1997, researchers proposed a simpler classification (the Villefranche nomenclature) that reduced the number of types to six and gave them descriptive names based on their major features. In 2017, the classification was updated to include rare forms of Ehlers-Danlos syndrome that were discovered more recently. The 2017 classification describes 13 types of Ehlers-Danlos syndrome.An unusually large range of joint movement (hypermobility) occurs in most forms of Ehlers-Danlos syndrome, and it is a hallmark feature of the hypermobile type. Infants and children with hypermobility often have weak muscle tone (hypotonia), which can delay the development of motor skills such as sitting, standing, and walking. The loose joints are unstable and prone to dislocation and chronic pain. In the arthrochalasia type of Ehlers-Danlos syndrome, infants have hypermobility and dislocations of both hips at birth.Many people with the Ehlers-Danlos syndromes have soft, velvety skin that is highly stretchy (elastic) and fragile. Affected individuals tend to bruise easily, and some types of the condition also cause abnormal scarring. People with the classical form of Ehlers-Danlos syndrome experience wounds that split open with little bleeding and leave scars that widen over time to create characteristic "cigarette paper" scars. The dermatosparaxis type of the disorder is characterized by loose skin that sags and wrinkles, and extra (redundant) folds of skin may be present.Some forms of Ehlers-Danlos syndrome, notably the vascular type and to a lesser extent the kyphoscoliotic, classical, and classical-like types, can cause unpredictable tearing (rupture) of blood vessels, leading to internal bleeding and other potentially life-threatening complications. The vascular type of Ehlers-Danlos syndrome is also associated with an increased risk of organ rupture, including tearing of the intestine and rupture of the uterus during pregnancy.Other types of Ehlers-Danlos syndrome have additional signs and symptoms. The cardiac-valvular type causes severe problems with the valves that control the movement of blood through the heart. People with the kyphoscoliotic type experience severe curvature of the spine that worsens over time and can interfere with breathing by restricting lung expansion. A type of Ehlers-Danlos syndrome called brittle cornea syndrome is characterized by thinness of the clear covering of the eye (the cornea) and other eye abnormalities. The spondylodysplastic type features short stature and skeletal abnormalities such as abnormally curved (bowed) limbs. Abnormalities of muscles, including hypotonia and permanently bent joints (contractures), are among the characteristic signs of the musculocontractural and myopathic forms of Ehlers-Danlos syndrome. The periodontal type causes abnormalities of the teeth and gums.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:134796895
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:134796895
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:134796895
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
TPM1
Variant:
c.*148G>T
rsID: rs7668
Ref Allele: G
Alt Allele: T
Freq: 3.1951%uncommon
CADD: 20.4
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 15:63066047
A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 15:63066047
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
MALT1
Variant:
c.-84G>A
rsID: rs56142402
Ref Allele: G
Alt Allele: A
Freq: 3.1967%uncommon
CADD: 14.57
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 29, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 18:58671560
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
TNFSF11
Variant:
c.924T>C
(p.Phe308=)
rsID: rs9562415
Ref Allele: T
Alt Allele: C
Freq: 3.207%uncommon
CADD: 12.23
ClinVar Submissions (1)
A rare genetic disorder inherited in an autosomal dominant, autosomal recessive, or X-linked recessive pattern. In the majority of cases it is caused by mutations in the CLCN7, TCIRG1, or IKBKG genes. It is characterized by excessive bone formation due to the failure of osteoclasts to resorb bone. It manifests with deformities, fractures, hepatosplenomegaly, anemia, and extramedullary hematopoiesis.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 13:42606888
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
GRHL2
Variant:
c.1572A>G
(p.Pro524=)
rsID: rs34213258
Ref Allele: A
Alt Allele: G
Freq: 3.2492%uncommon
CADD: 4.86
ClinVar Submissions (3)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 8:101644185
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
LRRK2
Variant:
c.*1446T>A
rsID: rs12422278
Ref Allele: T
Alt Allele: A
Freq: 3.2516%uncommon
CADD: 13.44
ClinVar Submissions (1)
LRRK2-related Parkinson disease (PD) is characterized by features consistent with PD of other etiologies: initial motor features of slowly progressive asymmetric tremor at rest and/or bradykinesia, cog-wheel muscle rigidity, postural instability, and gait abnormalities that may include festination and freezing. Non-motor symptoms in LRRK2-related PD occur with similar frequency as observed in typical PD of other etiologies. Onset is generally after age 50 years.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 12:40369211
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
CANT1
Variant:
c.*671T>C
rsID: rs114125762
Ref Allele: A
Alt Allele: G
Freq: 3.3002%uncommon
CADD: 7.02
ClinVar Submissions (1)
A rare osteochondrodysplasia characterized by short stature, joint laxity, multiple dislocations, vertebral and metaphyseal abnormalities, and advanced carpotarsal ossification. Two forms have been identified: type 1 caused by mutation in the gene CANT1 and type 2 caused by mutations in the gene XYLT1.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:78992879
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
CANT1
Variant:
c.*664T>C
rsID: rs79189369
Ref Allele: A
Alt Allele: G
Freq: 3.301%uncommon
CADD: 0.366
ClinVar Submissions (1)
A rare osteochondrodysplasia characterized by short stature, joint laxity, multiple dislocations, vertebral and metaphyseal abnormalities, and advanced carpotarsal ossification. Two forms have been identified: type 1 caused by mutation in the gene CANT1 and type 2 caused by mutations in the gene XYLT1.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:78992886
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
DNA2
Variant:
c.1971G>A
(p.Thr657=)
rsID: rs61855090
Ref Allele: C
Alt Allele: T
Freq: 3.3137%uncommon
CADD: 2.119
ClinVar Submissions (3)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Mar 08, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:68431874
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 08, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:68431874
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
NR1H4
Variant:
c.-1G>T
rsID: rs56163822
Ref Allele: G
Alt Allele: T
Freq: 3.3257%uncommon
CADD: 14.26
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 04, 2015
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:100493323
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
KARS
Variant:
c.1163-7C>T
rsID: rs16941301
Ref Allele: G
Alt Allele: A
Freq: 3.3281%uncommon
CADD: 12.22
ClinVar Submissions (4)
Last Evaluated: May 23, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:75631596
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 23, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:75631596
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 23, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:75631596
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
GNAT2
Variant:
c.319C>A
(p.Leu107Ile)
rsID: rs3738766
Ref Allele: G
Alt Allele: T
Freq: 3.3432%uncommon
CADD: 24.7
ClinVar Submissions (2)
Achromatopsia is characterized by reduced visual acuity, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma, eccentric fixation, and reduced or complete loss of color discrimination. All individuals with achromatopsia (achromats) have impaired color discrimination along all three axes of color vision corresponding to the three cone classes: the protan or long-wavelength-sensitive cone axis (red), the deutan or middle-wavelength-sensitive cone axis (green), and the tritan or short-wavelength-sensitive cone axis (blue). Most individuals have complete achromatopsia, with total lack of function of all three types of cones. Rarely, individuals have incomplete achromatopsia, in which one or more cone types may be partially functioning. The manifestations are similar to those of individuals with complete achromatopsia, but generally less severe. Hyperopia is common in achromatopsia. Nystagmus develops during the first few weeks after birth followed by increased sensitivity to bright light. Best visual acuity varies with severity of the disease; it is 20/200 or less in complete achromatopsia and may be as high as 20/80 in incomplete achromatopsia. Visual acuity is usually stable over time; both nystagmus and sensitivity to bright light may improve slightly. Although the fundus is usually normal, macular changes (which may show early signs of progression) and vessel narrowing may be present in some affected individuals. Defects in the macula are visible on optical coherence tomography.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:109608773
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:109608773
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
GLI3
Variant:
c.*847C>A
rsID: rs116986447
Ref Allele: G
Alt Allele: T
Freq: 3.3448%uncommon
CADD: 0.392
ClinVar Submissions (1)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963483
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963483
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963483
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
GLI3
Variant:
c.*1087A>T
rsID: rs76023240
Ref Allele: T
Alt Allele: A
Freq: 3.3472%uncommon
CADD: 0.456
ClinVar Submissions (1)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963243
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963243
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963243
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
GLI3
Variant:
c.4609C>T
(p.Arg1537Cys)
rsID: rs35364414
Ref Allele: G
Alt Allele: A
Freq: 3.3488%uncommon
CADD: 34
ClinVar Submissions (3)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964464
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964464
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964464
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964464
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964464
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964464
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
GLI3
Variant:
c.4020C>T
(p.Pro1340=)
rsID: rs35139358
Ref Allele: G
Alt Allele: A
Freq: 3.3504%uncommon
CADD: 0.228
ClinVar Submissions (3)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965053
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965053
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965053
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965053
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965053
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965053
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
GLI3
Variant:
c.4007G>A
(p.Gly1336Glu)
rsID: rs35280470
Ref Allele: C
Alt Allele: T
Freq: 3.3504%uncommon
CADD: 11.47
ClinVar Submissions (3)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965066
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965066
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965066
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965066
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965066
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965066
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
CANT1
Variant:
c.*964A>G
rsID: rs75126416
Ref Allele: T
Alt Allele: C
Freq: 3.3703%uncommon
CADD: 1.749
ClinVar Submissions (1)
A rare osteochondrodysplasia characterized by short stature, joint laxity, multiple dislocations, vertebral and metaphyseal abnormalities, and advanced carpotarsal ossification. Two forms have been identified: type 1 caused by mutation in the gene CANT1 and type 2 caused by mutations in the gene XYLT1.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:78992586
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
LTBP2
Variant:
c.2788+13C>T
rsID: rs78258030
Ref Allele: G
Alt Allele: A
Freq: 3.3838%uncommon
CADD: 0.024
ClinVar Submissions (2)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:74521898
Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterized by abnormalities of the lens of the eye, proportionate short stature, brachydactyly, and joint stiffness. The ocular problems, typically recognized in childhood, include microspherophakia (small spherical lens), myopia secondary to the abnormal shape of the lens, ectopia lentis (abnormal position of the lens), and glaucoma, which can lead to blindness. Height of adult males is 142-169 cm; height of adult females is 130-157 cm. Autosomal recessive and autosomal dominant WMS cannot be distinguished by clinical findings alone.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:74521898
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:74521898
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
GLI3
Variant:
c.*30G>T
rsID: rs77886553
Ref Allele: C
Alt Allele: A
Freq: 3.3846%uncommon
CADD: 0.253
ClinVar Submissions (2)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964300
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964300
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964300
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964300
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
GLI3
Variant:
c.*655A>G
rsID: rs77197280
Ref Allele: T
Alt Allele: C
Freq: 3.3854%uncommon
CADD: 1.053
ClinVar Submissions (1)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963675
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963675
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963675
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
GLI3
Variant:
c.*136T>A
rsID: rs78794712
Ref Allele: A
Alt Allele: T
Freq: 3.3854%uncommon
CADD: 9.772
ClinVar Submissions (1)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964194
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964194
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964194
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
GLI3
Variant:
c.*726A>G
rsID: rs118157739
Ref Allele: T
Alt Allele: C
Freq: 3.3918%uncommon
CADD: 0.103
ClinVar Submissions (1)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963604
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963604
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963604
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
GLI3
Variant:
c.2826G>C
(p.Pro942=)
rsID: rs34245321
Ref Allele: C
Alt Allele: G
Freq: 3.3958%uncommon
CADD: 6.879
ClinVar Submissions (4)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41966247
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41966247
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41966247
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41966247
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41966247
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41966247
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
MEFV
Variant:
c.442G>C
(p.Glu148Gln)
rsID: rs3743930
Ref Allele: C
Alt Allele: G
Freq: 3.4069%uncommon
CADD: 21.6
ClinVar Submissions (12)
Familial Mediterranean fever (FMF) is divided into two phenotypes: type 1 and type 2. FMF type 1 is characterized by recurrent short episodes of inflammation and serositis including fever, peritonitis, synovitis, pleuritis, and, rarely, pericarditis and meningitis. The symptoms and severity vary among affected individuals, sometimes even among members of the same family. Amyloidosis, which can lead to renal failure, is the most severe complication, if untreated. FMF type 2 is characterized by amyloidosis as the first clinical manifestation of FMF in an otherwise asymptomatic individual.
Last Evaluated: Dec 30, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 12
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 16:3254626
OMIM Allelic Variant: 608107.0005
Familial Mediterranean fever (FMF) is divided into two phenotypes: type 1 and type 2. FMF type 1 is characterized by recurrent short episodes of inflammation and serositis including fever, peritonitis, synovitis, pleuritis, and, rarely, pericarditis and meningitis. The symptoms and severity vary among affected individuals, sometimes even among members of the same family. Amyloidosis, which can lead to renal failure, is the most severe complication, if untreated. FMF type 2 is characterized by amyloidosis as the first clinical manifestation of FMF in an otherwise asymptomatic individual.
Last Evaluated: Dec 30, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 12
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 16:3254626
OMIM Allelic Variant: 608107.0005
Familial Mediterranean fever (FMF) is divided into two phenotypes: type 1 and type 2. FMF type 1 is characterized by recurrent short episodes of inflammation and serositis including fever, peritonitis, synovitis, pleuritis, and, rarely, pericarditis and meningitis. The symptoms and severity vary among affected individuals, sometimes even among members of the same family. Amyloidosis, which can lead to renal failure, is the most severe complication, if untreated. FMF type 2 is characterized by amyloidosis as the first clinical manifestation of FMF in an otherwise asymptomatic individual.
Last Evaluated: Dec 30, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 12
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 16:3254626
OMIM Allelic Variant: 608107.0005
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 30, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 12
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 16:3254626
OMIM Allelic Variant: 608107.0005
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 30, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 12
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 16:3254626
OMIM Allelic Variant: 608107.0005
The individual has two copies of the variant, which suggests they may manifest the associated condition or trait. This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Moderate clinical importance, Uncertain pathogenic — Some reports believe this cause Familial Mediterranean Fever in a recessive manner with reduced penetrance (i.e. not all get the disease). However, these reports lack strong statistical significance; other studies argue the variant is not associated with the disease.
Clinically Significant Conflicting/Uncertain
Homo
Gene:
SIM1
Variant:
c.-127T>C
rsID: rs41315244
Ref Allele: A
Alt Allele: G
Freq: 3.4762%uncommon
CADD: 8.681
ClinVar Submissions (1)
SHFYNG syndrome is an autosomal dominant multisystem disorder characterized by delayed psychomotor development, intellectual disability (ID), hypotonia, and behavioral abnormalities. Additional features include contractures, feeding difficulties, and variable dysmorphic facial features. The severity of the disorder is highly variable: some patients may die in utero with fetal akinesia, whereas others can live with moderate disability. Individuals are affected only if the mutation occurs on the paternal allele, since MAGEL2 is a maternally imprinted gene (summary by Fountain et al., 2017)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:100463595
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
NDUFAF4
Variant:
c.*387C>T
rsID: rs41288596
Ref Allele: G
Alt Allele: A
Freq: 3.4786%uncommon
CADD: 0.994
ClinVar Submissions (1)
Isolated complex I deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders (McFarland et al., 2004; Kirby et al., 2004). It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome (see 256000), Leber hereditary optic neuropathy (535000), and some forms of Parkinson disease (see 556500) (Loeffen et al., 2000; Pitkanen et al., 1996; Robinson, 1998). Genetic Heterogeneity of Complex I Deficiency Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible (summary by Haack et al., 2012). However, the majority of cases are caused by mutations in nuclear-encoded genes (Loeffen et al., 2000; Triepels et al., 2001). Complex I deficiency resulting from mutation in nuclear-encoded genes include MC1DN1, caused by mutation in the NDUFS4 gene (602694); MC1DN2 (618222), caused by mutation in the NDUFS8 gene (602141); MC1DN3 (618224), caused by mutation in the NDUFS7 gene (601825); MC1DN4 (618225), caused by mutation in the NDUFV1 gene (161015); MC1DN5 (618226), caused by mutation in the NDUFS1 gene (157655); MC1DN6 (618228), caused by mutation in the NDUFS2 gene (602985); MC1DN7 (618229), caused by mutation in the NDUFV2 gene (600532); MC1DN8 (618230), caused by mutation in the NDUFS3 gene (603846); MC1DN9 (618232), caused by mutation in the NDUFS6 gene (603848); MC1DN10 (618233), caused by mutation in the NDUFAF2 gene (609653); MC1DN11 (618234), caused by mutation in the NDUFAF1 gene (606934); MC1DN12 (301020), caused by mutation in the NDUFA1 gene (300078); MC1DN13 (618235), caused by mutation in the NDUFA2 gene (602137); MC1DN14 (618236), caused by mutation in the NDUFA11 gene (612638); MC1DN15 (618237), caused by mutation in the NDUFAF4 gene (611776); MC1DN16 (618238), caused by mutation in the NDUFAF5 gene (612360); MC1DN17 (618239), caused by mutation in the NDUFAF6 gene (612392); MC1DN18 (618240), caused by mutation in the NDUFAF3 gene (612911); MC1DN19 (618241), caused by mutation in the FOXRED1 gene (613622); MC1DN20 (611126), caused by mutation in the ACAD9 gene (611103); MC1DN21 (618242), caused by mutation in the NUBPL gene (613621); MC1DN22 (618243), caused by mutation in the NDUFA10 gene (603835); MC1DN23 (618244), caused by mutation in the NDUFA12 gene (614530); MC1DN24 (618245), caused by mutation in the NDUFB9 gene (601445); MC1DN25 (618246), caused by mutation in the NDUFB3 gene (603839); MC1DN26 (618247), caused by mutation in the NDUFA9 gene (603834); MC1DN27 (618248), caused by mutation in the MTFMT gene (611766); MC1DN28 (618249), caused by mutation in the NDUFA13 gene (609435); MC1DN29 (618250), caused by mutation in the TMEM126B gene (615533); MC1DN30 (301021), caused by mutation in the NDUFB11 gene (300403); MC1DN31 (618251), caused by mutation in the TIMMDC1 gene (615534); MC1DN32 (618252), caused by mutation in the NDUFB8 gene (602140); and MC1DN33 (618253), caused by mutation in the NDUFA6 gene (602138). Complex I deficiency with mitochondrial inheritance has been associated with mutation in 6 mitochondrial-encoded components of complex I: MTND1 (516000), MTND2 (516001), MTND3 (516002), MTND4 (516003), MTND5 (516005), MTND6 (516006). Most of these patients have a phenotype of Leber hereditary optic neuropathy (LHON; 535000) or Leigh syndrome. Features of complex I deficiency may also be caused by mutation in other mitochondrial genes, including MTTS2 (590085).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 6:96890717
This variant has conflicting interpretations of pathogenicity and should be interpreted with caution.
Conflicting/Uncertain
Hetero
Gene:
UNC13D
Variant:
c.-250C>T
rsID: rs57161046
Ref Allele: G
Alt Allele: A
Freq: 3.4842%uncommon
CADD: 10.48
ClinVar Submissions (1)
Familial hemophagocytic lymphohistiocytosis (FHL) is characterized by proliferation and infiltration of hyperactivated macrophages and T-lymphocytes manifesting as acute illness with prolonged fever, cytopenias, and hepatosplenomegaly. Onset is typically within the first months or years of life and, on occasion, in utero, although later childhood or adult onset is more common than previously suspected. Neurologic abnormalities may be present initially or may develop later; they may include increased intracranial pressure, irritability, neck stiffness, hypotonia, hypertonia, convulsions, cranial nerve palsies, ataxia, hemiplegia, quadriplegia, blindness, and coma. Rash and lymphadenopathy are less common. Other findings include liver dysfunction and bone marrow hemophagocytosis. The median survival of children with typical FHL, without treatment, is less than two months; progression of hemophagocytic lymphohistiocytosis and infection account for the majority of deaths in untreated individuals.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:75844587
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
CEP152
Variant:
c.*170T>C
rsID: rs2169757
Ref Allele: A
Alt Allele: G
Freq: 3.4874%uncommon
CADD: 14.28
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 15:48738079
A rare autosomal recessive inherited syndrome caused by mutations in the ATR gene, RBBP8 gene, CENPJ gene, CEP152 gene, CEP63 gene, NIN gene, DNA2 gene, or TRAIP gene. It is characterized by intrauterine growth retardation, dwarfism, microcephaly, mental retardation, and a "bird-headed" facial appearance.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 15:48738079
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
PPIB
Variant:
c.63C>A
(p.Ser21=)
rsID: rs4904
Ref Allele: G
Alt Allele: T
Freq: 3.5176%uncommon
CADD: 15.77
ClinVar Submissions (3)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 15:64162924
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 15:64162924
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 15:64162924
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
CASP10
Variant:
c.*1520C>T
rsID: rs41331447
Ref Allele: C
Alt Allele: T
Freq: 3.5256%uncommon
CADD: 2.697
ClinVar Submissions (1)
Autoimmune lymphoproliferative syndrome (ALPS), caused by defective lymphocyte homeostasis, is characterized by the following: Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age. Autoimmune disease, mostly directed toward blood cells. Lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma. In ALPS-FAS (the most common and best-characterized type of ALPS, associated with heterozygous germline pathogenic variants in FAS), non-malignant lymphoproliferation typically manifests in the first years of life, inexplicably waxes and wanes, and then often decreases without treatment in the second decade of life; in many affected individuals, however, neither splenomegaly nor the overall expansion of lymphocyte subsets in peripheral blood decreases. Although autoimmunity is often not present at the time of diagnosis or at the time of the most extensive lymphoproliferation, autoantibodies can be detected before autoimmune disease manifests clinically. In ALPS-FAS caused by homozygous or compound heterozygous (biallelic) pathogenic variants in FAS, severe lymphoproliferation occurs before, at, or shortly after birth, and usually results in death at an early age. ALPS-sFAS, resulting from somatic FAS pathogenic variants in selected cell populations, notably the alpha/beta double-negative T cells (a/ß-DNT cells), appears to be similar to ALPS-FAS resulting from heterozygous germline pathogenic variants in FAS, although lower incidence of splenectomy and lower lymphocyte counts have been reported in ALPS-sFAS and no cases of lymphoma have yet been published.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:201219261
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
SLC35C1
Variant:
c.*955C>A
rsID: rs76564550
Ref Allele: C
Alt Allele: A
Freq: 3.5288%uncommon
CADD: 0.087
ClinVar Submissions (1)
A genetically heterogeneous group of heritable disorders resulting from defects in protein N-glycosylation.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:45812290
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Homo
Gene:
ITGB3
Variant:
c.-7G>C
rsID: rs117052258
Ref Allele: G
Alt Allele: C
Freq: 3.5558%uncommon
CADD: 16.64
ClinVar Submissions (2)
Glanzmann thrombasthenia is an autosomal recessive bleeding disorder characterized by failure of platelet aggregation and by absent or diminished clot retraction. The abnormalities are related to quantitative or qualitative abnormalities of the GPIIb/IIIa platelet surface fibrinogen receptor complex resulting from mutations in either the GPIIb or GPIIIa genes (Rosenberg et al., 1997). See 187800 for discussion of a possible dominant form.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:47253855
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:47253855
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
TTBK2
Variant:
c.3251C>T
(p.Thr1084Met)
rsID: rs34348991
Ref Allele: G
Alt Allele: A
Freq: 3.5845%uncommon
CADD: 14.49
ClinVar Submissions (1)
Autosomal dominant cerebellar ataxia (ADCA) describes a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by a slowly progressive ataxia of gait, stance and limbs, dysarthria and/or oculomotor disorder, due to cerebellar degeneration in the absence of coexisting diseases. The degenerative process can be limited to the cerebellum (ADCA type 3) or may additionally involve the retina (ADCA type 2), optic nerve, ponto-medullary systems, basal ganglia, cerebral cortex, spinal tracts or peripheral nerves (ADCA type 1) (see these terms). In ACDA type 4 (see this term), a cerebellar syndrome is associated with epilepsy.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 15:42751995
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
RHBDF2
Variant:
c.*51G>C
rsID: rs76764510
Ref Allele: C
Alt Allele: G
Freq: 3.5925%uncommon
CADD: 5.369
ClinVar Submissions (1)
Palmoplantar keratoderma (PPK) is a complex group of hereditary syndromes that have been classified into diffuse, punctate, and focal forms according to the pattern of hyperkeratosis on the palms and soles (Lucker et al., 1994). For a discussion of phenotypic and genetic heterogeneity of palmoplantar keratoderma, see epidermolytic PPK (144200).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:76471582
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
GAN
Variant:
c.-75G>C
rsID: rs117642837
Ref Allele: G
Alt Allele: C
Freq: 3.5989%uncommon
CADD: 11.13
ClinVar Submissions (1)
Giant axonal neuropathy (GAN) is an early-onset fatal neurodegenerative disorder. GAN starts as severe peripheral motor and sensory neuropathy during infancy and evolves into central nervous system impairment (intellectual disability, seizures, cerebellar signs, and pyramidal tract signs). Most individuals become wheelchair dependent in the second decade of life and eventually bedridden with severe polyneuropathy, ataxia, and dementia. Death usually occurs in the third decade.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 16:81315039
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
MCPH1
Variant:
c.1728C>T
(p.Gly576=)
rsID: rs41313954
Ref Allele: C
Alt Allele: T
Freq: 3.5996%uncommon
CADD: 0.086
ClinVar Submissions (3)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:6445450
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:6445450
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
KCTD17
Variant:
c.918C>T
(p.Pro306=)
rsID: rs116956945
Ref Allele: C
Alt Allele: T
Freq: 3.61%uncommon
CADD: 17.13
ClinVar Submissions (1)
Myoclonic dystonia-26 is an autosomal dominant neurologic disorder characterized by onset of myoclonic jerks affecting the upper limbs in the first or second decade of life. The disorder is progressive, and patients later develop dystonia with predominant involvement of the craniocervical regions and sometimes the trunk and/or lower limbs. Dystonia dominates the clinical picture (summary by Mencacci et al., 2015).
Last Evaluated: Jul 19, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 22:37062546
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
PIGO
Variant:
c.3114C>T
(p.Leu1038=)
rsID: rs2298314
Ref Allele: G
Alt Allele: A
Freq: 3.6387%uncommon
CADD: 10.28
ClinVar Submissions (5)
Hyperphosphatasia with mental retardation syndrome-2 is an autosomal recessive disorder characterized by moderately to severely delayed psychomotor development, facial dysmorphism, brachytelephalangy, and increased serum alkaline phosphatase (hyperphosphatasia). Some patients may have additional features, such as cardiac septal defects or seizures (summary by Krawitz et al., 2012). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of hyperphosphatasia with mental retardation syndrome, see HPMRS1 (239300). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Last Evaluated: Aug 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:35089406
Mabry syndrome is a condition characterized by intellectual disability, distinctive facial features, increased levels of an enzyme called alkaline phosphatase in the blood (hyperphosphatasia), and other signs and symptoms.People with Mabry syndrome have intellectual disability that is often moderate to severe. They typically have little to no speech development and are delayed in the development of motor skills (such as sitting, crawling, and walking). Many affected individuals have low muscle tone (hypotonia) and develop recurrent seizures (epilepsy) in early childhood. Seizures are usually the generalized tonic-clonic type, which involve muscle rigidity, convulsions, and loss of consciousness.Individuals with Mabry syndrome have distinctive facial features that include wide-set eyes (hypertelorism), long openings of the eyelids (long palpebral fissures), a nose with a broad bridge and a rounded tip, downturned corners of the mouth, and a thin upper lip. These facial features usually become less pronounced over time.Hyperphosphatasia begins within the first year of life in people with Mabry syndrome. There are many different types of alkaline phosphatase found in tissues; the type that is increased in Mabry syndrome is called the tissue non-specific type and is found throughout the body. In affected individuals, alkaline phosphatase levels in the blood are usually increased by one to two times the normal amount, but can be up to 20 times higher than normal. The elevated enzyme levels remain relatively stable over a person's lifetime. Hyperphosphatasia appears to cause no negative health effects, but this finding can help health professionals diagnose Mabry syndrome.Another common feature of Mabry syndrome is shortened bones at the ends of fingers (brachytelephalangy), which can be seen on x-ray imaging. Underdeveloped fingernails (nail hypoplasia) may also occur. Sometimes, individuals with Mabry syndrome have abnormalities of the digestive system, including narrowing or blockage of the anus (anal stenosis or anal atresia) or Hirschsprung disease, a disorder that causes severe constipation or blockage of the intestine. Rarely, affected individuals experience hearing loss.The signs and symptoms of Mabry syndrome vary among affected individuals. Those who are least severely affected have only intellectual disability and hyperphosphatasia, without distinctive facial features or the other health problems listed above.
Last Evaluated: Aug 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:35089406
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:35089406
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
GDF6
Variant:
c.407-40C>G
rsID: rs11783820
Ref Allele: G
Alt Allele: C
Freq: 3.653%uncommon
CADD: 16.83
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 8:96145564
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
GHSR
Variant:
c.447C>G
(p.Leu149=)
rsID: rs2232169
Ref Allele: G
Alt Allele: C
Freq: 3.6538%uncommon
CADD: 7.244
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:172447967
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
MYO5B
Variant:
c.1206C>T
(p.Asn402=)
rsID: rs11082795
Ref Allele: G
Alt Allele: A
Freq: 3.6546%uncommon
CADD: 15.14
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 18:49974466
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
PNPLA2
Variant:
c.1167G>T
(p.Leu389=)
rsID: rs11554663
Ref Allele: G
Alt Allele: T
Freq: 3.657%uncommon
CADD: 6.877
ClinVar Submissions (2)
Neutral lipid storage disease with myopathy is an autosomal recessive muscle disorder characterized by adult onset of slowly progressive proximal muscle weakness affecting the upper and lower limbs and associated with increased serum creatine kinase; distal muscle weakness may also occur. About half of patients develop cardiomyopathy later in the disease course. Other variable features include diabetes mellitus, hepatic steatosis, hypertriglyceridemia, and possibly sensorineural hearing loss. Leukocytes and muscle cells show cytoplasmic accumulation of triglycerides (summary by Reilich et al., 2011). Neutral lipid storage disease with myopathy belongs to a group of disorders termed neutral lipid storage disorders (NLSDs). These disorders are characterized by the presence of triglyceride-containing cytoplasmic droplets in leukocytes and in other tissues, including bone marrow, skin, and muscle. Chanarin-Dorfman syndrome (CDS; 275630) is defined as NLSD with ichthyosis (NLSDI). Patients with NLSDM present with myopathy but without ichthyosis (summary by Fischer et al., 2007).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:824428
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:824428
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
CNGB1
Variant:
c.2882C>T
(p.Ala961Val)
rsID: rs112002818
Ref Allele: G
Alt Allele: A
Freq: 3.6737%uncommon
CADD: 21.2
ClinVar Submissions (2)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 16:57901538
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 16:57901538
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
PNPLA2
Variant:
c.678C>T
(p.Leu226=)
rsID: rs10902224
Ref Allele: C
Alt Allele: T
Freq: 3.6825%uncommon
CADD: 14.24
ClinVar Submissions (3)
Neutral lipid storage disease with myopathy is an autosomal recessive muscle disorder characterized by adult onset of slowly progressive proximal muscle weakness affecting the upper and lower limbs and associated with increased serum creatine kinase; distal muscle weakness may also occur. About half of patients develop cardiomyopathy later in the disease course. Other variable features include diabetes mellitus, hepatic steatosis, hypertriglyceridemia, and possibly sensorineural hearing loss. Leukocytes and muscle cells show cytoplasmic accumulation of triglycerides (summary by Reilich et al., 2011). Neutral lipid storage disease with myopathy belongs to a group of disorders termed neutral lipid storage disorders (NLSDs). These disorders are characterized by the presence of triglyceride-containing cytoplasmic droplets in leukocytes and in other tissues, including bone marrow, skin, and muscle. Chanarin-Dorfman syndrome (CDS; 275630) is defined as NLSD with ichthyosis (NLSDI). Patients with NLSDM present with myopathy but without ichthyosis (summary by Fischer et al., 2007).
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:822588
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:822588
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
ENPP1
Variant:
c.*2036A>G
rsID: rs73778611
Ref Allele: A
Alt Allele: G
Freq: 3.688%uncommon
CADD: 3.141
ClinVar Submissions (1)
Generalized arterial calcification of infancy (GACI) is characterized by infantile onset of widespread arterial calcification and/or narrowing of large- and medium-sized vessels resulting in cardiovascular findings (which can include heart failure, respiratory distress, edema, cyanosis, hypertension, and/or cardiomegaly). Additional findings can include extravascular calcifications (particularly periarticular), typical skin and retinal manifestations of pseudoxanthoma elasticum (PXE), hearing loss, and development of rickets after infancy. While mortality in infancy is high, survival into the second and third decade has been reported.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:131892547
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:131892547
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
HSPG2
Variant:
c.5899G>A
(p.Val1967Ile)
rsID: rs2229475
Ref Allele: C
Alt Allele: T
Freq: 3.7119%uncommon
CADD: 21.8
ClinVar Submissions (1)
A rare genetic primary bone dysplasia and lethal form of neonatal short-limbed dwarfism, with characteristics of anisospondyly, severe short stature and limb shortening, metaphyseal flaring and distinct dysmorphic features (flat facial appearance, abnormal ears, short neck, narrow thorax). Additional features may include other skeletal findings (for example joint contractures, bowed limbs, talipes equinovarus) and urogenital and cardiovascular abnormalities.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:21855402
Schwartz-Jampel syndrome is a rare condition characterized by permanent muscle stiffness (myotonia) and bone abnormalities known as chondrodysplasia. The signs and symptoms of this condition become apparent sometime after birth, usually in early childhood. Either muscle stiffness or chondrodysplasia can appear first. The muscle and bone abnormalities worsen in childhood, although most affected individuals have a normal lifespan. The specific features of Schwartz-Jampel syndrome vary widely.Myotonia involves continuous tensing (contraction) of muscles used for movement (skeletal muscles) throughout the body. This sustained muscle contraction causes stiffness that interferes with eating, sitting, walking, and other movements. Sustained contraction of muscles in the face leads to a fixed, "mask-like" facial expression with narrow eye openings (blepharophimosis) and pursed lips. This facial appearance is very specific to Schwartz-Jampel syndrome. Affected individuals may also be nearsighted and experience abnormal blinking or spasms of the eyelids (blepharospasm).Chondrodysplasia affects the development of the skeleton, particularly the long bones in the arms and legs and the bones of the hips. These bones are shortened and unusually wide at the ends, so affected individuals have short stature. The long bones may also be abnormally curved (bowed). Other bone abnormalities associated with Schwartz-Jampel syndrome include a protruding chest (pectus carinatum), abnormal curvature of the spine, flattened bones of the spine (platyspondyly), and joint abnormalities called contractures that further restrict movement.Researchers originally described two types of Schwartz-Jampel syndrome. Type 1 has the signs and symptoms described above, while type 2 has more severe bone abnormalities and other health problems and is usually life-threatening in early infancy. Researchers have since discovered that the condition they thought was Schwartz-Jampel syndrome type 2 is actually part of another disorder, Stüve-Wiedemann syndrome, which is caused by mutations in a different gene. They have recommended that the designation Schwartz-Jampel syndrome type 2 no longer be used.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:21855402
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
HSPG2
Variant:
c.6402G>A
(p.Val2134=)
rsID: rs12742444
Ref Allele: C
Alt Allele: T
Freq: 3.7135%uncommon
CADD: 1.397
ClinVar Submissions (2)
A rare genetic primary bone dysplasia and lethal form of neonatal short-limbed dwarfism, with characteristics of anisospondyly, severe short stature and limb shortening, metaphyseal flaring and distinct dysmorphic features (flat facial appearance, abnormal ears, short neck, narrow thorax). Additional features may include other skeletal findings (for example joint contractures, bowed limbs, talipes equinovarus) and urogenital and cardiovascular abnormalities.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:21854230
Schwartz-Jampel syndrome is a rare condition characterized by permanent muscle stiffness (myotonia) and bone abnormalities known as chondrodysplasia. The signs and symptoms of this condition become apparent sometime after birth, usually in early childhood. Either muscle stiffness or chondrodysplasia can appear first. The muscle and bone abnormalities worsen in childhood, although most affected individuals have a normal lifespan. The specific features of Schwartz-Jampel syndrome vary widely.Myotonia involves continuous tensing (contraction) of muscles used for movement (skeletal muscles) throughout the body. This sustained muscle contraction causes stiffness that interferes with eating, sitting, walking, and other movements. Sustained contraction of muscles in the face leads to a fixed, "mask-like" facial expression with narrow eye openings (blepharophimosis) and pursed lips. This facial appearance is very specific to Schwartz-Jampel syndrome. Affected individuals may also be nearsighted and experience abnormal blinking or spasms of the eyelids (blepharospasm).Chondrodysplasia affects the development of the skeleton, particularly the long bones in the arms and legs and the bones of the hips. These bones are shortened and unusually wide at the ends, so affected individuals have short stature. The long bones may also be abnormally curved (bowed). Other bone abnormalities associated with Schwartz-Jampel syndrome include a protruding chest (pectus carinatum), abnormal curvature of the spine, flattened bones of the spine (platyspondyly), and joint abnormalities called contractures that further restrict movement.Researchers originally described two types of Schwartz-Jampel syndrome. Type 1 has the signs and symptoms described above, while type 2 has more severe bone abnormalities and other health problems and is usually life-threatening in early infancy. Researchers have since discovered that the condition they thought was Schwartz-Jampel syndrome type 2 is actually part of another disorder, Stüve-Wiedemann syndrome, which is caused by mutations in a different gene. They have recommended that the designation Schwartz-Jampel syndrome type 2 no longer be used.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:21854230
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:21854230
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
HSPG2
Variant:
c.6673G>A
(p.Gly2225Ser)
rsID: rs35669711
Ref Allele: C
Alt Allele: T
Freq: 3.7199%uncommon
CADD: 6.537
ClinVar Submissions (1)
A rare genetic primary bone dysplasia and lethal form of neonatal short-limbed dwarfism, with characteristics of anisospondyly, severe short stature and limb shortening, metaphyseal flaring and distinct dysmorphic features (flat facial appearance, abnormal ears, short neck, narrow thorax). Additional features may include other skeletal findings (for example joint contractures, bowed limbs, talipes equinovarus) and urogenital and cardiovascular abnormalities.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:21852751
Schwartz-Jampel syndrome is a rare condition characterized by permanent muscle stiffness (myotonia) and bone abnormalities known as chondrodysplasia. The signs and symptoms of this condition become apparent sometime after birth, usually in early childhood. Either muscle stiffness or chondrodysplasia can appear first. The muscle and bone abnormalities worsen in childhood, although most affected individuals have a normal lifespan. The specific features of Schwartz-Jampel syndrome vary widely.Myotonia involves continuous tensing (contraction) of muscles used for movement (skeletal muscles) throughout the body. This sustained muscle contraction causes stiffness that interferes with eating, sitting, walking, and other movements. Sustained contraction of muscles in the face leads to a fixed, "mask-like" facial expression with narrow eye openings (blepharophimosis) and pursed lips. This facial appearance is very specific to Schwartz-Jampel syndrome. Affected individuals may also be nearsighted and experience abnormal blinking or spasms of the eyelids (blepharospasm).Chondrodysplasia affects the development of the skeleton, particularly the long bones in the arms and legs and the bones of the hips. These bones are shortened and unusually wide at the ends, so affected individuals have short stature. The long bones may also be abnormally curved (bowed). Other bone abnormalities associated with Schwartz-Jampel syndrome include a protruding chest (pectus carinatum), abnormal curvature of the spine, flattened bones of the spine (platyspondyly), and joint abnormalities called contractures that further restrict movement.Researchers originally described two types of Schwartz-Jampel syndrome. Type 1 has the signs and symptoms described above, while type 2 has more severe bone abnormalities and other health problems and is usually life-threatening in early infancy. Researchers have since discovered that the condition they thought was Schwartz-Jampel syndrome type 2 is actually part of another disorder, Stüve-Wiedemann syndrome, which is caused by mutations in a different gene. They have recommended that the designation Schwartz-Jampel syndrome type 2 no longer be used.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:21852751
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
FAM20C
Variant:
c.1672C>T
(p.Arg558Trp)
rsID: rs62644536
Ref Allele: C
Alt Allele: T
Freq: 3.7231%uncommon
CADD: 16.71
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 23, 2015
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:259897
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
HSPG2
Variant:
c.6552G>A
(p.Thr2184=)
rsID: rs34443576
Ref Allele: C
Alt Allele: T
Freq: 3.7247%uncommon
CADD: 0.48
ClinVar Submissions (1)
A rare genetic primary bone dysplasia and lethal form of neonatal short-limbed dwarfism, with characteristics of anisospondyly, severe short stature and limb shortening, metaphyseal flaring and distinct dysmorphic features (flat facial appearance, abnormal ears, short neck, narrow thorax). Additional features may include other skeletal findings (for example joint contractures, bowed limbs, talipes equinovarus) and urogenital and cardiovascular abnormalities.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:21852958
Schwartz-Jampel syndrome is a rare condition characterized by permanent muscle stiffness (myotonia) and bone abnormalities known as chondrodysplasia. The signs and symptoms of this condition become apparent sometime after birth, usually in early childhood. Either muscle stiffness or chondrodysplasia can appear first. The muscle and bone abnormalities worsen in childhood, although most affected individuals have a normal lifespan. The specific features of Schwartz-Jampel syndrome vary widely.Myotonia involves continuous tensing (contraction) of muscles used for movement (skeletal muscles) throughout the body. This sustained muscle contraction causes stiffness that interferes with eating, sitting, walking, and other movements. Sustained contraction of muscles in the face leads to a fixed, "mask-like" facial expression with narrow eye openings (blepharophimosis) and pursed lips. This facial appearance is very specific to Schwartz-Jampel syndrome. Affected individuals may also be nearsighted and experience abnormal blinking or spasms of the eyelids (blepharospasm).Chondrodysplasia affects the development of the skeleton, particularly the long bones in the arms and legs and the bones of the hips. These bones are shortened and unusually wide at the ends, so affected individuals have short stature. The long bones may also be abnormally curved (bowed). Other bone abnormalities associated with Schwartz-Jampel syndrome include a protruding chest (pectus carinatum), abnormal curvature of the spine, flattened bones of the spine (platyspondyly), and joint abnormalities called contractures that further restrict movement.Researchers originally described two types of Schwartz-Jampel syndrome. Type 1 has the signs and symptoms described above, while type 2 has more severe bone abnormalities and other health problems and is usually life-threatening in early infancy. Researchers have since discovered that the condition they thought was Schwartz-Jampel syndrome type 2 is actually part of another disorder, Stüve-Wiedemann syndrome, which is caused by mutations in a different gene. They have recommended that the designation Schwartz-Jampel syndrome type 2 no longer be used.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:21852958
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
HSPG2
Variant:
c.8026-5T>C
rsID: rs35917892
Ref Allele: A
Alt Allele: G
Freq: 3.7271%uncommon
CADD: 0.297
ClinVar Submissions (1)
A rare genetic primary bone dysplasia and lethal form of neonatal short-limbed dwarfism, with characteristics of anisospondyly, severe short stature and limb shortening, metaphyseal flaring and distinct dysmorphic features (flat facial appearance, abnormal ears, short neck, narrow thorax). Additional features may include other skeletal findings (for example joint contractures, bowed limbs, talipes equinovarus) and urogenital and cardiovascular abnormalities.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:21847497
Schwartz-Jampel syndrome is a rare condition characterized by permanent muscle stiffness (myotonia) and bone abnormalities known as chondrodysplasia. The signs and symptoms of this condition become apparent sometime after birth, usually in early childhood. Either muscle stiffness or chondrodysplasia can appear first. The muscle and bone abnormalities worsen in childhood, although most affected individuals have a normal lifespan. The specific features of Schwartz-Jampel syndrome vary widely.Myotonia involves continuous tensing (contraction) of muscles used for movement (skeletal muscles) throughout the body. This sustained muscle contraction causes stiffness that interferes with eating, sitting, walking, and other movements. Sustained contraction of muscles in the face leads to a fixed, "mask-like" facial expression with narrow eye openings (blepharophimosis) and pursed lips. This facial appearance is very specific to Schwartz-Jampel syndrome. Affected individuals may also be nearsighted and experience abnormal blinking or spasms of the eyelids (blepharospasm).Chondrodysplasia affects the development of the skeleton, particularly the long bones in the arms and legs and the bones of the hips. These bones are shortened and unusually wide at the ends, so affected individuals have short stature. The long bones may also be abnormally curved (bowed). Other bone abnormalities associated with Schwartz-Jampel syndrome include a protruding chest (pectus carinatum), abnormal curvature of the spine, flattened bones of the spine (platyspondyly), and joint abnormalities called contractures that further restrict movement.Researchers originally described two types of Schwartz-Jampel syndrome. Type 1 has the signs and symptoms described above, while type 2 has more severe bone abnormalities and other health problems and is usually life-threatening in early infancy. Researchers have since discovered that the condition they thought was Schwartz-Jampel syndrome type 2 is actually part of another disorder, Stüve-Wiedemann syndrome, which is caused by mutations in a different gene. They have recommended that the designation Schwartz-Jampel syndrome type 2 no longer be used.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:21847497
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
HSPG2
Variant:
c.7806C>A
(p.Val2602=)
rsID: rs12737091
Ref Allele: G
Alt Allele: T
Freq: 3.7271%uncommon
CADD: 4.09
ClinVar Submissions (1)
A rare genetic primary bone dysplasia and lethal form of neonatal short-limbed dwarfism, with characteristics of anisospondyly, severe short stature and limb shortening, metaphyseal flaring and distinct dysmorphic features (flat facial appearance, abnormal ears, short neck, narrow thorax). Additional features may include other skeletal findings (for example joint contractures, bowed limbs, talipes equinovarus) and urogenital and cardiovascular abnormalities.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:21848025
Schwartz-Jampel syndrome is a rare condition characterized by permanent muscle stiffness (myotonia) and bone abnormalities known as chondrodysplasia. The signs and symptoms of this condition become apparent sometime after birth, usually in early childhood. Either muscle stiffness or chondrodysplasia can appear first. The muscle and bone abnormalities worsen in childhood, although most affected individuals have a normal lifespan. The specific features of Schwartz-Jampel syndrome vary widely.Myotonia involves continuous tensing (contraction) of muscles used for movement (skeletal muscles) throughout the body. This sustained muscle contraction causes stiffness that interferes with eating, sitting, walking, and other movements. Sustained contraction of muscles in the face leads to a fixed, "mask-like" facial expression with narrow eye openings (blepharophimosis) and pursed lips. This facial appearance is very specific to Schwartz-Jampel syndrome. Affected individuals may also be nearsighted and experience abnormal blinking or spasms of the eyelids (blepharospasm).Chondrodysplasia affects the development of the skeleton, particularly the long bones in the arms and legs and the bones of the hips. These bones are shortened and unusually wide at the ends, so affected individuals have short stature. The long bones may also be abnormally curved (bowed). Other bone abnormalities associated with Schwartz-Jampel syndrome include a protruding chest (pectus carinatum), abnormal curvature of the spine, flattened bones of the spine (platyspondyly), and joint abnormalities called contractures that further restrict movement.Researchers originally described two types of Schwartz-Jampel syndrome. Type 1 has the signs and symptoms described above, while type 2 has more severe bone abnormalities and other health problems and is usually life-threatening in early infancy. Researchers have since discovered that the condition they thought was Schwartz-Jampel syndrome type 2 is actually part of another disorder, Stüve-Wiedemann syndrome, which is caused by mutations in a different gene. They have recommended that the designation Schwartz-Jampel syndrome type 2 no longer be used.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:21848025
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
HSPG2
Variant:
c.8939T>A
(p.Leu2980His)
rsID: rs2229489
Ref Allele: A
Alt Allele: T
Freq: 3.7311%uncommon
CADD: 18.06
ClinVar Submissions (2)
A rare genetic primary bone dysplasia and lethal form of neonatal short-limbed dwarfism, with characteristics of anisospondyly, severe short stature and limb shortening, metaphyseal flaring and distinct dysmorphic features (flat facial appearance, abnormal ears, short neck, narrow thorax). Additional features may include other skeletal findings (for example joint contractures, bowed limbs, talipes equinovarus) and urogenital and cardiovascular abnormalities.
Last Evaluated: May 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:21842352
Schwartz-Jampel syndrome is a rare condition characterized by permanent muscle stiffness (myotonia) and bone abnormalities known as chondrodysplasia. The signs and symptoms of this condition become apparent sometime after birth, usually in early childhood. Either muscle stiffness or chondrodysplasia can appear first. The muscle and bone abnormalities worsen in childhood, although most affected individuals have a normal lifespan. The specific features of Schwartz-Jampel syndrome vary widely.Myotonia involves continuous tensing (contraction) of muscles used for movement (skeletal muscles) throughout the body. This sustained muscle contraction causes stiffness that interferes with eating, sitting, walking, and other movements. Sustained contraction of muscles in the face leads to a fixed, "mask-like" facial expression with narrow eye openings (blepharophimosis) and pursed lips. This facial appearance is very specific to Schwartz-Jampel syndrome. Affected individuals may also be nearsighted and experience abnormal blinking or spasms of the eyelids (blepharospasm).Chondrodysplasia affects the development of the skeleton, particularly the long bones in the arms and legs and the bones of the hips. These bones are shortened and unusually wide at the ends, so affected individuals have short stature. The long bones may also be abnormally curved (bowed). Other bone abnormalities associated with Schwartz-Jampel syndrome include a protruding chest (pectus carinatum), abnormal curvature of the spine, flattened bones of the spine (platyspondyly), and joint abnormalities called contractures that further restrict movement.Researchers originally described two types of Schwartz-Jampel syndrome. Type 1 has the signs and symptoms described above, while type 2 has more severe bone abnormalities and other health problems and is usually life-threatening in early infancy. Researchers have since discovered that the condition they thought was Schwartz-Jampel syndrome type 2 is actually part of another disorder, Stüve-Wiedemann syndrome, which is caused by mutations in a different gene. They have recommended that the designation Schwartz-Jampel syndrome type 2 no longer be used.
Last Evaluated: May 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:21842352
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:21842352
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
TRAP1
Variant:
c.543+6C>T
rsID: rs61753379
Ref Allele: G
Alt Allele: A
Freq: 3.7613%uncommon
CADD: 10.01
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 23, 2016
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:3679713
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
CETP
Variant:
c.1168G>C
(p.Ala390Pro)
rsID: rs5880
Ref Allele: G
Alt Allele: C
Freq: 3.7693%uncommon
CADD: 24.3
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:56981179
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Low clinical importance, Likely pathogenic — This variant is associated with slightly lower HDL (good) cholesterol, although it has a negligible effect (around 2 mg/dl).
Benign
Hetero
Gene:
GLI3
Variant:
c.1509C>T
(p.Asn503=)
rsID: rs34020684
Ref Allele: G
Alt Allele: A
Freq: 3.786%uncommon
CADD: 1.282
ClinVar Submissions (3)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41978737
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41978737
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41978737
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41978737
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41978737
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41978737
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
GP9
Variant:
c.132G>A
(p.Thr44=)
rsID: rs6069
Ref Allele: G
Alt Allele: A
Freq: 3.8035%uncommon
CADD: 0.274
ClinVar Submissions (2)
Bernard-Soulier syndrome is an autosomal recessive bleeding disorder caused by a defect in or deficiency of the platelet membrane von Willebrand factor (VWF; 613160) receptor complex, glycoprotein Ib (GP Ib). GP Ib is composed of 4 subunits encoded by 4 separate genes: GP1BA, GP1BB, GP9, and GP5 (173511). Genetic Heterogeneity of Platelet-Type Bleeding Disorders Inherited platelet disorders are a heterogeneous group of bleeding disorders affecting platelet number, function, or both. Functional defects can involve platelet receptors, signaling pathways, cytoskeletal proteins, granule contents, activation, or aggregation (review by Cox et al., 2011 and Nurden and Nurden, 2011). Platelet-type bleeding disorders include Bernard-Soulier syndrome (BDPLT1); Glanzmann thrombasthenia (BDPLT2; 273800), caused by mutation in the ITGA2B (607759) or ITGB3 (173470) gene; pseudo-von Willebrand disease (BDPLT3; 177820), caused by mutation in the GP1BA gene (606672); gray platelet syndrome (BDPLT4; 139090), caused by mutation in the NBEAL2 gene (614169); Quebec platelet disorder (BDPLT5; 601709), caused by tandem duplication of the PLAU gene (191840); May-Hegglin anomaly (BDPLT6; 155100), caused by mutation in the MYH9 gene (160775); Scott syndrome (BDPLT7; 262890), caused by mutation in the TMEM16F gene (608663); BDPLT8 (609821), caused by mutation in the P2RY12 gene (600515); BDPLT9 (614200), associated with deficiency of the glycoprotein Ia/IIa receptor (see ITGA2; 192974); glycoprotein IV deficiency (BDPLT10; 608404), caused by mutation in the CD36 gene (173510); BDPLT11 (614201), caused by mutation in the GP6 gene (605546); BDPLT12 (605735), associated with a deficiency of platelet COX1 (176805); susceptibility to BDPLT13 (614009), caused by mutation in the TBXA2R gene (188070); BDPLT14 (614158), associated with deficiency of thromboxane synthetase (TBXAS1; 274180); BDPLT15 (615193), caused by mutation in the ACTN1 gene (102575); BDPLT16 (187800), caused by mutation in the ITGA2B (607759) or ITGB3 (173470) gene; BDPLT17 (187900), caused by mutation in the GFI1B gene (604383); BDPLT18 (615888), caused by mutation in the RASGRP2 gene (605577); BDPLT19 (616176), caused by mutation in the PRKACG gene (176893); BDPLT20 (616913), caused by mutation in the SLFN14 gene (614958); and BDPLT21 (617443), caused by mutation in the FLI1 gene (193067). See reviews by Rao (2003), Cox et al. (2011), and Nurden and Nurden (2011). For a discussion of the genetic heterogeneity of hereditary thrombocytopenia, see THC1 (313900).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:129061871
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:129061871
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
MAPT
Variant:
c.689A>G
(p.Gln230Arg)
rsID: rs63750072
Ref Allele: A
Alt Allele: G
Freq: 3.8067%uncommon
CADD: 21.9
ClinVar Submissions (3)
Frontotemporal dementia (FTD) refers to a clinical manifestation of the pathologic finding of frontotemporal lobar degeneration (FTLD). FTD, the most common subtype of FTLD, is a behavioral variant characterized by changes in social and personal conduct with loss of volition, executive dysfunction, loss of abstract thought, and decreased speech output. A second clinical subtype of FTLD is 'semantic dementia,' characterized by specific loss of comprehension of language and impaired facial and object recognition. A third clinical subtype of FTLD is 'primary progressive aphasia' (PPA), characterized by a reduction in speech production, speech errors, and word retrieval difficulties resulting in mutism and an inability to communicate. All subtypes have relative preservation of memory, at least in the early stages. FTLD is often associated with parkinsonism or motor neuron disease (MND) resembling amyotrophic lateral sclerosis (ALS; 105400) (reviews by Tolnay and Probst, 2002 and Mackenzie and Rademakers, 2007). Mackenzie et al. (2009, 2010) provided a classification of FTLD subtypes according to the neuropathologic findings (see PATHOGENESIS below). Clinical Variability of Tauopathies Tauopathies comprise a clinically variable group of neurodegenerative diseases characterized neuropathologically by accumulation of abnormal MAPT-positive inclusions in nerve and/or glial cells. In addition to frontotemporal dementia, semantic dementia, and PPA, different clinical syndromes with overlapping features have been described, leading to confusion in the terminology (Tolnay and Probst, 2002). Other terms used historically include parkinsonism and dementia with pallidopontonigral degeneration (PPND) (Wszolek et al., 1992); disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC) (Lynch et al., 1994); frontotemporal dementia with parkinsonism (FLDEM) (Yamaoka et al., 1996); and multiple system tauopathy with presenile dementia (MSTD) (Spillantini et al., 1997). These disorders are characterized by variable degrees of frontal lobe dementia, parkinsonism, motor neuron disease, and amyotrophy. Other neurodegenerative associated with mutations in the MAPT gene include Pick disease (172700) and progressive supranuclear palsy (PSP; 601104), Inherited neurodegenerative tauopathies linked to chromosome 17 and caused by mutation in the MAPT gene have also been collectively termed 'FTDP17' (Lee et al., 2001). Kertesz (2003) suggested the term 'Pick complex' to represent the overlapping syndromes of FTD, primary progressive aphasia (PPA), corticobasal degeneration (CBD), PSP, and FTD with motor neuron disease. He noted that frontotemporal dementia may also be referred to as 'clinical Pick disease' and that the term 'Pick disease' should be restricted to the pathologic finding of Pick bodies. Genetic Heterogeneity of Frontotemporal Lobar Degeneration Mutations in several different genes can cause frontotemporal dementia and frontotemporal lobar degeneration, with or without motor neuron disease. See FTLD with TDP43 inclusions (607485), caused by mutation in the GRN gene (138945) on chromosome 17q21; FTLD mapping to chromosome 3 (600795), caused by mutation in the CHMP2B gene (609512); inclusion body myopathy with Paget disease and FTD (IBMPFD; 167320), caused by mutation in the VCP gene (601023) on chromosome 9p13; ALS6 (608030), caused by mutation in the FUS gene (137070) on 16p11; ALS10 (612069), caused by mutation in the TARDBP gene (605078) on 1p36; and FTDALS (105550), caused by mutation in the C9ORF72 gene (614260) on 9p. In 1 family with FTD, a mutation was identified in the presenilin-1 gene (PSEN1; 104311) on chromosome 14, which is usually associated with a familial form of early-onset Alzheimer disease (AD3; 607822).
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:45983493
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:45983493
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:45983493
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Low clinical importance, Uncertain benign — Common polymorphism.
Benign
Hetero
Gene:
LFNG
Variant:
c.1002C>T
(p.Tyr334=)
rsID: rs61743870
Ref Allele: C
Alt Allele: T
Freq: 3.8099%uncommon
CADD: 13.63
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:2526850
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
CTH
Variant:
c.*544G>A
rsID: rs45615634
Ref Allele: G
Alt Allele: A
Freq: 3.8298%uncommon
CADD: 1.081
ClinVar Submissions (1)
Cystathioninuria, an autosomal recessive phenotype with no striking pathologic features, is characterized by abnormal accumulation of plasma cystathionine, leading to increased urinary excretion. Because of the inconsistency and wide variety of disease associations, cystathioninuria is considered to be a benign biochemical anomaly (Mudd et al., 2001).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:70439671
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
OTOF
Variant:
c.2613C>T
(p.Leu871=)
rsID: rs2272068
Ref Allele: G
Alt Allele: A
Freq: 3.8489%uncommon
CADD: 12.62
ClinVar Submissions (3)
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:26476954
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:26476954
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
BIN1
Variant:
c.894G>A
(p.Ser298=)
rsID: rs2228955
Ref Allele: C
Alt Allele: T
Freq: 3.8521%uncommon
CADD: 0.054
ClinVar Submissions (6)
Centronuclear myopathy is a condition characterized by muscle weakness (myopathy) and wasting (atrophy) in the skeletal muscles, which are the muscles used for movement. The severity of centronuclear myopathy varies among affected individuals, even among members of the same family.People with centronuclear myopathy begin experiencing muscle weakness at any time from birth to early adulthood. The muscle weakness slowly worsens over time and can lead to delayed development of motor skills, such as crawling or walking; muscle pain during exercise; and difficulty walking. Some affected individuals may need wheelchair assistance as the muscles atrophy and weakness becomes more severe. In rare instances, the muscle weakness improves over time.Some people with centronuclear myopathy experience mild to severe breathing problems related to the weakness of muscles needed for breathing. People with centronuclear myopathy may have droopy eyelids (ptosis) and weakness in other facial muscles, including the muscles that control eye movement. People with this condition may also have foot abnormalities, a high arch in the roof of the mouth (high-arched palate), and abnormal side-to-side curvature of the spine (scoliosis). Rarely, individuals with centronuclear myopathy have a weakened heart muscle (cardiomyopathy), disturbances in nerve function (neuropathy), or intellectual disability.A key feature of centronuclear myopathy is the displacement of the nucleus in muscle cells, which can be viewed under a microscope. Normally the nucleus is found at the edges of the rod-shaped muscle cells, but in people with centronuclear myopathy the nucleus is located in the center of these cells. How the change in location of the nucleus affects muscle cell function is unknown.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:127059119
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:127059119
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
UNC13D
Variant:
c.1977C>T
(p.Thr659=)
rsID: rs2290770
Ref Allele: G
Alt Allele: A
Freq: 3.876%uncommon
CADD: 6.788
ClinVar Submissions (3)
Familial hemophagocytic lymphohistiocytosis (FHL) is characterized by proliferation and infiltration of hyperactivated macrophages and T-lymphocytes manifesting as acute illness with prolonged fever, cytopenias, and hepatosplenomegaly. Onset is typically within the first months or years of life and, on occasion, in utero, although later childhood or adult onset is more common than previously suspected. Neurologic abnormalities may be present initially or may develop later; they may include increased intracranial pressure, irritability, neck stiffness, hypotonia, hypertonia, convulsions, cranial nerve palsies, ataxia, hemiplegia, quadriplegia, blindness, and coma. Rash and lymphadenopathy are less common. Other findings include liver dysfunction and bone marrow hemophagocytosis. The median survival of children with typical FHL, without treatment, is less than two months; progression of hemophagocytic lymphohistiocytosis and infection account for the majority of deaths in untreated individuals.
Last Evaluated: Jul 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:75834935
Familial hemophagocytic lymphohistiocytosis (FHL) is characterized by proliferation and infiltration of hyperactivated macrophages and T-lymphocytes manifesting as acute illness with prolonged fever, cytopenias, and hepatosplenomegaly. Onset is typically within the first months or years of life and, on occasion, in utero, although later childhood or adult onset is more common than previously suspected. Neurologic abnormalities may be present initially or may develop later; they may include increased intracranial pressure, irritability, neck stiffness, hypotonia, hypertonia, convulsions, cranial nerve palsies, ataxia, hemiplegia, quadriplegia, blindness, and coma. Rash and lymphadenopathy are less common. Other findings include liver dysfunction and bone marrow hemophagocytosis. The median survival of children with typical FHL, without treatment, is less than two months; progression of hemophagocytic lymphohistiocytosis and infection account for the majority of deaths in untreated individuals.
Last Evaluated: Jul 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:75834935
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:75834935
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
TMIE
Variant:
c.*51C>T
rsID: rs56002857
Ref Allele: C
Alt Allele: T
Freq: 3.8776%uncommon
CADD: 0.401
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:46709739
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
HSD17B4
Variant:
c.2199C>T
(p.Tyr733=)
rsID: rs12714
Ref Allele: C
Alt Allele: T
Freq: 3.884%uncommon
CADD: 1.662
ClinVar Submissions (7)
D-bifunctional protein deficiency is a disorder of peroxisomal fatty acid beta-oxidation. See also peroxisomal acyl-CoA oxidase deficiency (264470), caused by mutation in the ACOX1 gene (609751) on chromosome 17q25. The clinical manifestations of these 2 deficiencies are similar to those of disorders of peroxisomal assembly, including X-linked adrenoleukodystrophy (ALD; 300100), Zellweger cerebrohepatorenal syndrome (see 214100) and neonatal adrenoleukodystrophy (NALD; see 601539) (Watkins et al., 1995). DBP deficiency has been classified into 3 subtypes depending upon the deficient enzyme activity. Type I is a deficiency of both 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase; type II is a deficiency of hydratase activity alone; and type III is a deficiency of dehydrogenase activity alone. Virtually all patients with types I, II, and III have a severe phenotype characterized by infantile-onset of hypotonia, seizures, and abnormal facial features, and most die before age 2 years. McMillan et al. (2012) proposed a type IV deficiency on the basis of less severe features; these patients have a phenotype reminiscent of Perrault syndrome (PRLTS1; 233400). Pierce et al. (2010) noted that Perrault syndrome and DBP deficiency overlap clinically and suggested that DBP deficiency may be underdiagnosed.
Last Evaluated: May 24, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:119541982
D-bifunctional protein deficiency is a disorder of peroxisomal fatty acid beta-oxidation. See also peroxisomal acyl-CoA oxidase deficiency (264470), caused by mutation in the ACOX1 gene (609751) on chromosome 17q25. The clinical manifestations of these 2 deficiencies are similar to those of disorders of peroxisomal assembly, including X-linked adrenoleukodystrophy (ALD; 300100), Zellweger cerebrohepatorenal syndrome (see 214100) and neonatal adrenoleukodystrophy (NALD; see 601539) (Watkins et al., 1995). DBP deficiency has been classified into 3 subtypes depending upon the deficient enzyme activity. Type I is a deficiency of both 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase; type II is a deficiency of hydratase activity alone; and type III is a deficiency of dehydrogenase activity alone. Virtually all patients with types I, II, and III have a severe phenotype characterized by infantile-onset of hypotonia, seizures, and abnormal facial features, and most die before age 2 years. McMillan et al. (2012) proposed a type IV deficiency on the basis of less severe features; these patients have a phenotype reminiscent of Perrault syndrome (PRLTS1; 233400). Pierce et al. (2010) noted that Perrault syndrome and DBP deficiency overlap clinically and suggested that DBP deficiency may be underdiagnosed.
Last Evaluated: May 24, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:119541982
Perrault syndrome is a rare condition that causes different patterns of signs and symptoms in affected males and females. A key feature of this condition is hearing loss, which occurs in both males and females. Affected females also have abnormalities of the ovaries. Neurological problems occur in some affected males and females.In Perrault syndrome, the problems with hearing are caused by changes in the inner ear, which is known as sensorineural hearing loss. The impairment usually affects both ears and can be present at birth or begin in early childhood. Unless hearing is completely impaired at birth, the hearing problems worsen over time.Females with Perrault syndrome have abnormal or missing ovaries (ovarian dysgenesis), although their external genitalia are normal. Severely affected girls do not begin menstruation by age 16 (primary amenorrhea), and most never have a menstrual period. Less severely affected women have an early loss of ovarian function (primary ovarian insufficiency); their menstrual periods begin in adolescence, but they become less frequent and eventually stop before age 40. Women with Perrault syndrome may have difficulty conceiving or be unable to have biological children (infertile).Neurological problems in individuals with Perrault syndrome can include intellectual disability, difficulty with balance and coordinating movements (ataxia), and loss of sensation and weakness in the limbs (peripheral neuropathy). However, not everyone with this condition has neurological problems.
Last Evaluated: May 24, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:119541982
Perrault syndrome is characterized by sensorineural hearing loss (SNHL) in males and females and ovarian dysfunction in females. SNHL is bilateral and ranges from profound with prelingual (congenital) onset to moderate with early-childhood onset. When onset is in early childhood, hearing loss can be progressive. Ovarian dysfunction ranges from gonadal dysgenesis (absent or streak gonads) manifesting as primary amenorrhea to primary ovarian insufficiency (POI) defined as cessation of menses before age 40 years. Fertility in affected males is reported as normal (although the number of reported males is limited). Neurologic features described in some individuals with Perrault syndrome include learning difficulties and developmental delay, cerebellar ataxia, and motor and sensory peripheral neuropathy.
Last Evaluated: May 24, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:119541982
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 24, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:119541982
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 24, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:119541982
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
MAPT
Variant:
c.1815G>A
(p.Pro605=)
rsID: rs11568305
Ref Allele: G
Alt Allele: A
Freq: 3.8887%uncommon
CADD: 1.079
ClinVar Submissions (5)
Frontotemporal dementia (FTD) refers to a clinical manifestation of the pathologic finding of frontotemporal lobar degeneration (FTLD). FTD, the most common subtype of FTLD, is a behavioral variant characterized by changes in social and personal conduct with loss of volition, executive dysfunction, loss of abstract thought, and decreased speech output. A second clinical subtype of FTLD is 'semantic dementia,' characterized by specific loss of comprehension of language and impaired facial and object recognition. A third clinical subtype of FTLD is 'primary progressive aphasia' (PPA), characterized by a reduction in speech production, speech errors, and word retrieval difficulties resulting in mutism and an inability to communicate. All subtypes have relative preservation of memory, at least in the early stages. FTLD is often associated with parkinsonism or motor neuron disease (MND) resembling amyotrophic lateral sclerosis (ALS; 105400) (reviews by Tolnay and Probst, 2002 and Mackenzie and Rademakers, 2007). Mackenzie et al. (2009, 2010) provided a classification of FTLD subtypes according to the neuropathologic findings (see PATHOGENESIS below). Clinical Variability of Tauopathies Tauopathies comprise a clinically variable group of neurodegenerative diseases characterized neuropathologically by accumulation of abnormal MAPT-positive inclusions in nerve and/or glial cells. In addition to frontotemporal dementia, semantic dementia, and PPA, different clinical syndromes with overlapping features have been described, leading to confusion in the terminology (Tolnay and Probst, 2002). Other terms used historically include parkinsonism and dementia with pallidopontonigral degeneration (PPND) (Wszolek et al., 1992); disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC) (Lynch et al., 1994); frontotemporal dementia with parkinsonism (FLDEM) (Yamaoka et al., 1996); and multiple system tauopathy with presenile dementia (MSTD) (Spillantini et al., 1997). These disorders are characterized by variable degrees of frontal lobe dementia, parkinsonism, motor neuron disease, and amyotrophy. Other neurodegenerative associated with mutations in the MAPT gene include Pick disease (172700) and progressive supranuclear palsy (PSP; 601104), Inherited neurodegenerative tauopathies linked to chromosome 17 and caused by mutation in the MAPT gene have also been collectively termed 'FTDP17' (Lee et al., 2001). Kertesz (2003) suggested the term 'Pick complex' to represent the overlapping syndromes of FTD, primary progressive aphasia (PPA), corticobasal degeneration (CBD), PSP, and FTD with motor neuron disease. He noted that frontotemporal dementia may also be referred to as 'clinical Pick disease' and that the term 'Pick disease' should be restricted to the pathologic finding of Pick bodies. Genetic Heterogeneity of Frontotemporal Lobar Degeneration Mutations in several different genes can cause frontotemporal dementia and frontotemporal lobar degeneration, with or without motor neuron disease. See FTLD with TDP43 inclusions (607485), caused by mutation in the GRN gene (138945) on chromosome 17q21; FTLD mapping to chromosome 3 (600795), caused by mutation in the CHMP2B gene (609512); inclusion body myopathy with Paget disease and FTD (IBMPFD; 167320), caused by mutation in the VCP gene (601023) on chromosome 9p13; ALS6 (608030), caused by mutation in the FUS gene (137070) on 16p11; ALS10 (612069), caused by mutation in the TARDBP gene (605078) on 1p36; and FTDALS (105550), caused by mutation in the C9ORF72 gene (614260) on 9p. In 1 family with FTD, a mutation was identified in the presenilin-1 gene (PSEN1; 104311) on chromosome 14, which is usually associated with a familial form of early-onset Alzheimer disease (AD3; 607822).
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:45996652
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:45996652
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:45996652
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:45996652
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
LPL
Variant:
c.*371T>C
rsID: rs3289
Ref Allele: T
Alt Allele: C
Freq: 3.8903%uncommon
CADD: 10.63
ClinVar Submissions (1)
Familial lipoprotein lipase (LPL) deficiency usually presents in childhood and is characterized by very severe hypertriglyceridemia with episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. Clearance of chylomicrons from the plasma is impaired, causing triglycerides to accumulate in plasma and the plasma to have a milky (lactescent or lipemic) appearance. Symptoms usually resolve with restriction of total dietary fat to =20 g/day.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 8:19965681
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
RYR2
Variant:
c.13564-41A>G
rsID: rs114289907
Ref Allele: A
Alt Allele: G
Freq: 3.915%uncommon
CADD: 0.538
ClinVar Submissions (3)
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by episodic syncope occurring during exercise or acute emotion in individuals without structural cardiac abnormalities. The underlying cause of these episodes is the onset of fast ventricular tachycardia (bidirectional or polymorphic). Spontaneous recovery may occur when these arrhythmias self-terminate. In other instances, ventricular tachycardia may degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation is not readily available. The mean age of onset of symptoms (usually a syncopal episode) is between age seven and twelve years; onset as late as the fourth decade of life has been reported. If untreated, CPVT is highly lethal, as approximately 30% of affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. Sudden death may be the first manifestation of the disease.
Last Evaluated: Jan 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:237792064
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:237792064
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
MCM4
Variant:
c.*358T>C
rsID: rs17287761
Ref Allele: T
Alt Allele: C
Freq: 3.9254%uncommon
CADD: 0.329
ClinVar Submissions (1)
Immunodeficiency-54 is an autosomal recessive primary immunodeficiency characterized by severe intra- and extrauterine growth retardation, microcephaly, decreased numbers of natural killer (NK) cells, and recurrent viral infections, most often affecting the respiratory tract and leading to respiratory failure. Affected individuals also have adrenal insufficiency requiring corticosteroid replacement therapy and may have an increased susceptibility to cancer. Laboratory studies of patient cells showed a DNA repair defect (summary by Gineau et al., 2012).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 8:47977136
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
THRA
Variant:
c.351C>T
(p.Ala117=)
rsID: rs2230701
Ref Allele: C
Alt Allele: T
Freq: 3.9294%uncommon
CADD: 3.512
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 18, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:40083963
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
SLC6A1
Variant:
c.651G>T
(p.Thr217=)
rsID: rs6344
Ref Allele: G
Alt Allele: T
Freq: 3.9333%uncommon
CADD: 5.351
ClinVar Submissions (2)
Last Evaluated: Jun 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:11022405
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:11022405
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
DOCK7
Variant:
c.4256-4A>G
rsID: rs17123688
Ref Allele: T
Alt Allele: C
Freq: 3.9453%uncommon
CADD: 6.886
ClinVar Submissions (2)
Last Evaluated: Aug 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:62510677
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:62510677
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
DMP1
Variant:
c.*280C>T
rsID: rs76370957
Ref Allele: C
Alt Allele: T
Freq: 3.9461%uncommon
CADD: 3.085
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 4:87663600
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
COL9A1
Variant:
c.1066-3T>C
rsID: rs16868869
Ref Allele: A
Alt Allele: G
Freq: 3.9516%uncommon
CADD: 1.04
ClinVar Submissions (4)
Autosomal dominant multiple epiphyseal dysplasia (MED) presents in early childhood, usually with pain in the hips and/or knees after exercise. Affected children complain of fatigue with long-distance walking. Waddling gait may be present. Adult height is either in the lower range of normal or mildly shortened. The limbs are relatively short in comparison to the trunk. Pain and joint deformity progress, resulting in early-onset osteoarthritis, particularly of the large weight-bearing joints.
Last Evaluated: Aug 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:70272091
Last Evaluated: Aug 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:70272091
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:70272091
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:70272091
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
TGFBR2
Variant:
c.1167C>T
(p.Asn389=)
rsID: rs2228048
Ref Allele: C
Alt Allele: T
Freq: 3.954%uncommon
CADD: 0.07
ClinVar Submissions (5)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:30672350
Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:30672350
Marfan syndrome, a systemic disorder of connective tissue with a high degree of clinical variability, comprises a broad phenotypic continuum ranging from mild (features of Marfan syndrome in one or a few systems) to severe and rapidly progressive neonatal multiorgan disease. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. Ocular findings include myopia (the most common ocular feature); ectopia lentis (seen in approximately 60% of affected individuals); and an increased risk for retinal detachment, glaucoma, and early cataracts. Skeletal system manifestations include bone overgrowth and joint laxity; disproportionately long extremities for the size of the trunk (dolichostenomelia); overgrowth of the ribs that can push the sternum in (pectus excavatum) or out (pectus carinatum); and scoliosis that ranges from mild to severe and progressive. The major morbidity and early mortality in the Marfan syndrome relate to the cardiovascular system and include dilatation of the aorta at the level of the sinuses of Valsalva (predisposing to aortic tear and rupture), mitral valve prolapse with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery. Severe and prolonged regurgitation of the mitral and/or aortic valve can predispose to left ventricular dysfunction and occasionally heart failure. With proper management, the life expectancy of someone with Marfan syndrome approximates that of the general population.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:30672350
Familial thoracic aortic aneurysm and dissection (familial TAAD) involves problems with the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. Familial TAAD affects the upper part of the aorta, near the heart. This part of the aorta is called the thoracic aorta because it is located in the chest (thorax). Other vessels that carry blood from the heart to the rest of the body (arteries) can also be affected.In familial TAAD, the aorta can become weakened and stretched (aortic dilatation), which can lead to a bulge in the blood vessel wall (an aneurysm). Aortic dilatation may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection), allowing blood to flow abnormally between the layers. These aortic abnormalities are potentially life-threatening because they can decrease blood flow to other parts of the body such as the brain or other vital organs, or cause the aorta to break open (rupture).The occurrence and timing of these aortic abnormalities vary, even within the same affected family. They can begin in childhood or not occur until late in life. Aortic dilatation is generally the first feature of familial TAAD to develop, although in some affected individuals dissection occurs with little or no aortic dilatation.Aortic aneurysms usually have no symptoms. However, depending on the size, growth rate, and location of these abnormalities, they can cause pain in the jaw, neck, chest, or back; swelling in the arms, neck, or head; difficult or painful swallowing; hoarseness; shortness of breath; wheezing; a chronic cough; or coughing up blood. Aortic dissections usually cause severe, sudden chest or back pain, and may also result in unusually pale skin (pallor), a very faint pulse, numbness or tingling (paresthesias) in one or more limbs, or paralysis.Familial TAAD may not be associated with other signs and symptoms. However, some individuals in affected families show mild features of related conditions called Marfan syndrome or Loeys-Dietz syndrome. These features include tall stature, stretch marks on the skin, an unusually large range of joint movement (joint hypermobility), and either a sunken or protruding chest. Occasionally, people with familial TAAD develop aneurysms in the brain or in the section of the aorta located in the abdomen (abdominal aorta). Some people with familial TAAD have heart abnormalities that are present from birth (congenital). Affected individuals may also have a soft out-pouching in the lower abdomen (inguinal hernia), an abnormal curvature of the spine (scoliosis), or a purplish skin discoloration (livedo reticularis) caused by abnormalities in the tiny blood vessels of the skin (dermal capillaries). However, these conditions are also common in the general population. Depending on the genetic cause of familial TAAD in particular families, they may have an increased risk of developing blockages in smaller arteries, which can lead to heart attack and stroke.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:30672350
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:30672350
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
GHSR
Variant:
c.60C>T
(p.Asp20=)
rsID: rs2232165
Ref Allele: G
Alt Allele: A
Freq: 3.954%uncommon
CADD: 1.255
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:172448354
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
USH2A
Variant:
c.9343A>G
(p.Thr3115Ala)
rsID: rs56032526
Ref Allele: T
Alt Allele: C
Freq: 3.9572%uncommon
CADD: 4.081
ClinVar Submissions (4)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 06, 2014
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:215838019
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 06, 2014
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:215838019
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
GHSR
Variant:
c.*796A>T
rsID: rs58550930
Ref Allele: T
Alt Allele: A
Freq: 3.9923%uncommon
CADD: 0.219
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:172444365
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
FLCN
Variant:
c.*393G>A
rsID: rs12602675
Ref Allele: C
Alt Allele: T
Freq: 3.9931%uncommon
CADD: 1.917
ClinVar Submissions (1)
The clinical characteristics of Birt-Hogg-Dubé syndrome (BHDS) include cutaneous manifestations (fibrofolliculomas, trichodiscomas/angiofibromas, perifollicular fibromas, and acrochordons), pulmonary cysts/history of pneumothorax, and various types of renal tumors. Disease severity can vary significantly even within the same family. Skin lesions typically appear during the third and fourth decades of life and typically increase in size and number with age. Lung cysts are mostly bilateral and multifocal; most individuals are asymptomatic but at high risk for spontaneous pneumothorax. Individuals with BHDS are at a sevenfold increased risk for renal tumors that are typically bilateral and multifocal and usually slow growing; median age of tumor diagnosis is 48 years. The most common renal tumors are a hybrid of oncocytoma and chromophobe histologic cell types (so-called oncocytic hybrid tumor) and chromophobe histologic cell types. Some families have renal tumor and/or autosomal dominant spontaneous pneumothorax without cutaneous manifestations.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:17213262
Pneumothorax occurring without traumatic injury to the chest or lung.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:17213262
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Homo
Gene:
BEST1;FTH1
Variant:
c.*222C>T
rsID: rs17156609
Ref Allele: G
Alt Allele: A
Freq: 4.009%uncommon
CADD: 6.795
ClinVar Submissions (1)
Accumulation of iron in the tissues. It may be a manifestation of an inherited disorder (e.g., hemochromatosis) or acquired (in patients with repeated blood transfusions). Symptoms include hepatomegaly, arthritis, diabetes mellitus, and bronzed skin. If untreated it has a progressive course and may lead to death.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:61964505
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:61964505
Best vitelliform macular dystrophy is a slowly progressive macular dystrophy with onset generally in childhood and sometimes in later teenage years. Affected individuals initially have normal vision followed by decreased central visual acuity and metamorphopsia. Individuals retain normal peripheral vision and dark adaptation. Age of onset and severity of vision loss show inter- and intrafamilial variability.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:61964505
Autosomal dominant vitreoretinochoroidopathy (ADVIRC) is a disorder that affects several parts of the eyes, including the clear gel that fills the eye (the vitreous), the light-sensitive tissue that lines the back of the eye (the retina), and the network of blood vessels within the retina (the choroid). The eye abnormalities in ADVIRC can lead to varying degrees of vision impairment, from mild reduction to complete loss, although some people with the condition have normal vision.The signs and symptoms of ADVIRC vary, even among members of the same family. Many affected individuals have microcornea, in which the clear front covering of the eye (cornea) is small and abnormally curved. The area behind the cornea can also be abnormally small, which is described as a shallow anterior chamber. Individuals with ADVIRC can develop increased pressure in the eyes (glaucoma) or clouding of the lens of the eye (cataract). In addition, some people have breakdown (degeneration) of the vitreous or the choroid.A characteristic feature of ADVIRC, visible with a special eye exam, is a circular band of excess coloring (hyperpigmentation) in the retina. This feature can help physicians diagnose the disorder. Affected individuals may also have white spots on the retina.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:61964505
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
IL2RA
Variant:
c.*1880C>G
rsID: rs12722607
Ref Allele: G
Alt Allele: C
Freq: 4.0249%uncommon
CADD: 0.305
ClinVar Submissions (1)
Immunodeficiency-41 is an autosomal recessive complex disorder of immune dysregulation. Affected individuals present in infancy with recurrent viral, fungal, and bacterial infections, lymphadenopathy, and variable autoimmune features, such as autoimmune enteropathy and eczematous skin lesions. Immunologic studies show a defect in T-cell regulation (summary by Goudy et al., 2013).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 10:6010992
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
KCNQ2
Variant:
c.*295C>T
rsID: rs34690549
Ref Allele: G
Alt Allele: A
Freq: 4.0576%uncommon
CADD: 0.053
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 20:63406349
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
TLR4
Variant:
c.1196C>T
(p.Thr399Ile)
rsID: rs4986791
Ref Allele: C
Alt Allele: T
Freq: 4.0735%uncommon
CADD: 7.987
ClinVar Submissions (2)
Last Evaluated: May 06, 2013
Review Status: no assertion criteria provided
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:117713324
OMIM Allelic Variant: 603030.0002
Last Evaluated: May 06, 2013
Review Status: no assertion criteria provided
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:117713324
OMIM Allelic Variant: 603030.0002
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
RGR
Variant:
c.734C>T
(p.Ser245Phe)
rsID: rs61730895
Ref Allele: C
Alt Allele: T
Freq: 4.0743%uncommon
CADD: 14.53
ClinVar Submissions (2)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 10:84257984
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 10:84257984
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
POLR3A
Variant:
c.*1862G>A
rsID: rs12572507
Ref Allele: C
Alt Allele: T
Freq: 4.0846%uncommon
CADD: 2.714
ClinVar Submissions (1)
POLR3-related leukodystrophy, a hypomyelinating leukodystrophy with specific features on brain MRI, is characterized by varying combinations of four major clinical findings: Neurologic dysfunction, typically predominated by motor dysfunction (progressive cerebellar dysfunction, and to a lesser extent extrapyramidal [i.e., dystonia], pyramidal [i.e., spasticity] and cognitive dysfunctions). Abnormal dentition (delayed dentition, hypodontia, oligodontia, and abnormally placed or shaped teeth). Endocrine abnormalities such as short stature (in ~50% of individuals) with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as delayed, arrested, or absent puberty. Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe. POLR3-related leukodystrophy and 4H leukodystrophy are the two recognized terms for five previously described overlapping clinical phenotypes (initially described as distinct entities before their molecular basis was known). These include: Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); Ataxia, delayed dentition, and hypomyelination (ADDH); Tremor-ataxia with central hypomyelination (TACH); Leukodystrophy with oligodontia (LO); Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). Age of onset is typically in early childhood but later-onset cases have also been reported. An infant with Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) was recently reported to have pathogenic variants in POLR3A on exome sequencing. Confirmation of this as a very severe form of POLR3-related leukodystrophy awaits replication in other individuals with a clinical diagnosis of Wiedemann-Rautenstrauch syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 10:77975616
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
PSPH
Variant:
c.-632C>T
rsID: rs34822782
Ref Allele: G
Alt Allele: A
Freq: 4.0894%uncommon
CADD: 7.076
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:56051478
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
HYAL1
Variant:
c.766G>A
(p.Gly256Arg)
rsID: rs116482870
Ref Allele: C
Alt Allele: T
Freq: 4.1388%uncommon
CADD: 8.268
ClinVar Submissions (2)
An autosomal recessive lysosomal storage disease caused by mutation(s) in the HYAL1 gene, encoding hyaluronidase-1. It is characterized by short stature and hyaluronidase deficiency.
Last Evaluated: Apr 19, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:50302191
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Apr 19, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:50302191
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
PHOX2B
Variant:
c.*1347A>G
rsID: rs62412180
Ref Allele: T
Alt Allele: C
Freq: 4.142%uncommon
CADD: 23.1
ClinVar Submissions (1)
Congenital central hypoventilation syndrome (CCHS) is a rare disorder of respiratory and autonomic regulation. It is typically characterized by a classic presentation in newborns and, rarely, a milder later-onset (LO-CCHS) presentation in toddlers, children, and adults. Classic CCHS presents in newborns as: Apparent hypoventilation with monotonous respiratory rates and shallow breathing either during sleep only or while awake as well as asleep; Autonomic nervous system dysregulation (ANSD); and In some individuals, altered development of neural crest-derived structures (i.e., Hirschsprung disease) and/or tumors of neural crest origin (neuroblastoma, ganglioneuroma, and ganglioneuroblastoma). Individuals with CCHS who have been diagnosed as newborns and ventilated conservatively and consistently throughout childhood have now reached the age of 20 to 30 years; they are highly functional and live independently. LO-CCHS manifests as nocturnal alveolar hypoventilation and mild ANSD. Individuals with LO-CCHS who were not identified until age 20 years or older have now reached the age of 30 to 55 years.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:41744460
ALK-related neuroblastic tumor susceptibility is characterized by increased risk for neuroblastic tumors including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Neuroblastoma is a more malignant tumor and ganglioneuroma a more benign tumor. Depending on the histologic findings, ganglioneuroblastoma can behave in a more aggressive fashion, like neuroblastoma, or in a benign fashion, like ganglioneuroma. Preliminary data from the ten reported families with ALK-related neuroblastic tumor susceptibility suggest an overall penetrance of approximately 57% with the risk for neuroblastic tumor development highest in infancy and decreasing by late childhood.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:41744460
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
IL2RA
Variant:
c.*677G>A
rsID: rs12719919
Ref Allele: C
Alt Allele: T
Freq: 4.1667%uncommon
CADD: 1.208
ClinVar Submissions (1)
Immunodeficiency-41 is an autosomal recessive complex disorder of immune dysregulation. Affected individuals present in infancy with recurrent viral, fungal, and bacterial infections, lymphadenopathy, and variable autoimmune features, such as autoimmune enteropathy and eczematous skin lesions. Immunologic studies show a defect in T-cell regulation (summary by Goudy et al., 2013).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 10:6012195
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
SLC5A1
Variant:
c.1899G>A
(p.Thr633=)
rsID: rs33943816
Ref Allele: G
Alt Allele: A
Freq: 4.1802%uncommon
CADD: 0.107
ClinVar Submissions (2)
Glucose/galactose malabsorption (GGM) is a rare autosomal recessive disorder caused by a defect in glucose and galactose transport across the intestinal brush border. Patients with GGM present with neonatal onset of severe life-threatening watery diarrhea and dehydration. If diagnosed and treated properly, patients can fully recover and show normal growth and development (summary by Xin and Wang, 2011).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 22:32110117
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 22:32110117
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
PDGFRA
Variant:
c.368-3C>T
rsID: rs55947416
Ref Allele: C
Alt Allele: T
Freq: 4.1874%uncommon
CADD: 16.12
ClinVar Submissions (2)
Gastrointestinal stromal tumors are mesenchymal tumors found in the gastrointestinal tract that originate from the interstitial cells of Cajal, the pacemaker cells that regulate peristalsis in the digestive tract. Approximately 70% of GISTs develop in the stomach, 20% in the small intestine, and less than 10% in the esophagus, colon, and rectum. GISTs are typically more cellular than other gastrointestinal sarcomas. They occur predominantly in patients who are 40 to 70 years old but in rare cases may occur in younger persons (Miettinen et al., 1999, 1999). GISTs can also be seen in neurofibromatosis-1 (NF1; 162200) due to mutations in the NF1 gene, and are thus distinct from the GISTs described here. Sandberg and Bridge (2002) reviewed the cytogenetics and molecular genetics of gastrointestinal stromal tumors. Coffey et al. (2007) reviewed the clinical features, pathogenesis, and molecular treatments of Menetrier disease (137280) and GIST, both of which are hyperproliferative disorders of the stomach caused by dysregulated receptor tyrosine kinases.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:54263664
PDGFRA-associated chronic eosinophilic leukemia is a form of blood cell cancer characterized by an elevated number of cells called eosinophils in the blood. These cells help fight infections by certain parasites and are involved in the inflammation associated with allergic reactions. However, these circumstances do not account for the increased number of eosinophils in PDGFRA-associated chronic eosinophilic leukemia.Another characteristic feature of PDGFRA-associated chronic eosinophilic leukemia is organ damage caused by the excess eosinophils. Eosinophils release substances to aid in the immune response, but the release of excessive amounts of these substances causes damage to one or more organs, most commonly the heart, skin, lungs, or nervous system. Eosinophil-associated organ damage can lead to a heart condition known as eosinophilic endomyocardial disease, skin rashes, coughing, difficulty breathing, swelling (edema) in the lower limbs, confusion, changes in behavior, or impaired movement or sensations. People with PDGFRA-associated chronic eosinophilic leukemia can also have an enlarged spleen (splenomegaly) and elevated levels of certain chemicals called vitamin B12 and tryptase in the blood.Some people with PDGFRA-associated chronic eosinophilic leukemia have an increased number of other types of white blood cells, such as neutrophils or mast cells. Occasionally, people with PDGFRA-associated chronic eosinophilic leukemia develop other blood cell cancers, such as acute myeloid leukemia or B-cell or T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma.PDGFRA-associated chronic eosinophilic leukemia is often grouped with a related condition called hypereosinophilic syndrome. These two conditions have very similar signs and symptoms; however, the cause of hypereosinophilic syndrome is unknown.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:54263664
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:54263664
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
POLR3A
Variant:
c.2286C>T
(p.His762=)
rsID: rs16935534
Ref Allele: G
Alt Allele: A
Freq: 4.1898%uncommon
CADD: 0.232
ClinVar Submissions (1)
POLR3-related leukodystrophy, a hypomyelinating leukodystrophy with specific features on brain MRI, is characterized by varying combinations of four major clinical findings: Neurologic dysfunction, typically predominated by motor dysfunction (progressive cerebellar dysfunction, and to a lesser extent extrapyramidal [i.e., dystonia], pyramidal [i.e., spasticity] and cognitive dysfunctions). Abnormal dentition (delayed dentition, hypodontia, oligodontia, and abnormally placed or shaped teeth). Endocrine abnormalities such as short stature (in ~50% of individuals) with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as delayed, arrested, or absent puberty. Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe. POLR3-related leukodystrophy and 4H leukodystrophy are the two recognized terms for five previously described overlapping clinical phenotypes (initially described as distinct entities before their molecular basis was known). These include: Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); Ataxia, delayed dentition, and hypomyelination (ADDH); Tremor-ataxia with central hypomyelination (TACH); Leukodystrophy with oligodontia (LO); Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). Age of onset is typically in early childhood but later-onset cases have also been reported. An infant with Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) was recently reported to have pathogenic variants in POLR3A on exome sequencing. Confirmation of this as a very severe form of POLR3-related leukodystrophy awaits replication in other individuals with a clinical diagnosis of Wiedemann-Rautenstrauch syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:78002270
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
POLR3A
Variant:
c.2394T>C
(p.Cys798=)
rsID: rs35536566
Ref Allele: A
Alt Allele: G
Freq: 4.1945%uncommon
CADD: 12.73
ClinVar Submissions (1)
POLR3-related leukodystrophy, a hypomyelinating leukodystrophy with specific features on brain MRI, is characterized by varying combinations of four major clinical findings: Neurologic dysfunction, typically predominated by motor dysfunction (progressive cerebellar dysfunction, and to a lesser extent extrapyramidal [i.e., dystonia], pyramidal [i.e., spasticity] and cognitive dysfunctions). Abnormal dentition (delayed dentition, hypodontia, oligodontia, and abnormally placed or shaped teeth). Endocrine abnormalities such as short stature (in ~50% of individuals) with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as delayed, arrested, or absent puberty. Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe. POLR3-related leukodystrophy and 4H leukodystrophy are the two recognized terms for five previously described overlapping clinical phenotypes (initially described as distinct entities before their molecular basis was known). These include: Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); Ataxia, delayed dentition, and hypomyelination (ADDH); Tremor-ataxia with central hypomyelination (TACH); Leukodystrophy with oligodontia (LO); Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). Age of onset is typically in early childhood but later-onset cases have also been reported. An infant with Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) was recently reported to have pathogenic variants in POLR3A on exome sequencing. Confirmation of this as a very severe form of POLR3-related leukodystrophy awaits replication in other individuals with a clinical diagnosis of Wiedemann-Rautenstrauch syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:78001060
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
PLIN1
Variant:
c.580C>G
(p.Pro194Ala)
rsID: rs6496589
Ref Allele: G
Alt Allele: C
Freq: 4.1953%uncommon
CADD: 11.28
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 15:89669998
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
FRAS1
Variant:
c.7371+11T>C
rsID: rs7664505
Ref Allele: T
Alt Allele: C
Freq: 4.2065%uncommon
CADD: 0.12
ClinVar Submissions (3)
Fraser syndrome is an autosomal recessive malformation disorder characterized by cryptophthalmos, syndactyly, and abnormalities of the respiratory and urogenital tract (summary by van Haelst et al., 2008). Genetic Heterogeneity of Fraser Syndrome Fraser syndrome-2 (FRASRS2) is caused by mutation in the FREM2 gene (608945) on chromosome 13q13, and Fraser syndrome-3 (FRASRS3) is caused by mutation in the GRIP1 gene (604597) on chromosome 12q14. See Bowen syndrome (211200) for a comparable but probably distinct syndrome of multiple congenital malformations.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:78470102
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:78470102
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
PKD1
Variant:
c.2730C>T
(p.Asp910=)
rsID: rs35965348
Ref Allele: G
Alt Allele: A
Freq: 4.2145%uncommon
CADD: 0.072
ClinVar Submissions (4)
Autosomal dominant polycystic kidney disease (ADPKD) is generally a late-onset multisystem disorder characterized by bilateral renal cysts, liver cysts, and an increased risk of intracranial aneurysms. Other manifestations include: cysts in the pancreas, seminal vesicles, and arachnoid membrane; dilatation of the aortic root and dissection of the thoracic aorta; mitral valve prolapse; and abdominal wall hernias. Renal manifestations include hypertension, renal pain, and renal insufficiency. Approximately 50% of individuals with ADPKD have end-stage renal disease (ESRD) by age 60 years. The prevalence of liver cysts increases with age and occasionally results in clinically significant severe polycystic liver disease (PLD). Overall the prevalence of intracranial aneurysms is fivefold higher than in the general population and further increased in those with a positive family history of aneurysms or subarachnoid hemorrhage. There is substantial variability in the severity of renal disease and other extrarenal manifestations even within the same family.
Last Evaluated: Jun 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:2114293
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:2114293
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:2114293
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
PRKN
Variant:
c.*2492A>G
rsID: rs117341007
Ref Allele: T
Alt Allele: C
Freq: 4.22%uncommon
CADD: 1.285
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:161347607
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
PKD1
Variant:
c.2700G>A
(p.Pro900=)
rsID: rs35667726
Ref Allele: C
Alt Allele: T
Freq: 4.22%uncommon
CADD: 0.018
ClinVar Submissions (4)
Autosomal dominant polycystic kidney disease (ADPKD) is generally a late-onset multisystem disorder characterized by bilateral renal cysts, liver cysts, and an increased risk of intracranial aneurysms. Other manifestations include: cysts in the pancreas, seminal vesicles, and arachnoid membrane; dilatation of the aortic root and dissection of the thoracic aorta; mitral valve prolapse; and abdominal wall hernias. Renal manifestations include hypertension, renal pain, and renal insufficiency. Approximately 50% of individuals with ADPKD have end-stage renal disease (ESRD) by age 60 years. The prevalence of liver cysts increases with age and occasionally results in clinically significant severe polycystic liver disease (PLD). Overall the prevalence of intracranial aneurysms is fivefold higher than in the general population and further increased in those with a positive family history of aneurysms or subarachnoid hemorrhage. There is substantial variability in the severity of renal disease and other extrarenal manifestations even within the same family.
Last Evaluated: Jun 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:2114323
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:2114323
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:2114323
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
ENPP1
Variant:
c.*2282G>A
rsID: rs73778612
Ref Allele: G
Alt Allele: A
Freq: 4.2423%uncommon
CADD: 2.015
ClinVar Submissions (1)
Generalized arterial calcification of infancy (GACI) is characterized by infantile onset of widespread arterial calcification and/or narrowing of large- and medium-sized vessels resulting in cardiovascular findings (which can include heart failure, respiratory distress, edema, cyanosis, hypertension, and/or cardiomegaly). Additional findings can include extravascular calcifications (particularly periarticular), typical skin and retinal manifestations of pseudoxanthoma elasticum (PXE), hearing loss, and development of rickets after infancy. While mortality in infancy is high, survival into the second and third decade has been reported.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:131892793
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:131892793
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
FAS
Variant:
c.222A>G
(p.Thr74=)
rsID: rs2229521
Ref Allele: A
Alt Allele: G
Freq: 4.2447%uncommon
CADD: 5.465
ClinVar Submissions (1)
Autoimmune lymphoproliferative syndrome (ALPS), caused by defective lymphocyte homeostasis, is characterized by the following: Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age. Autoimmune disease, mostly directed toward blood cells. Lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma. In ALPS-FAS (the most common and best-characterized type of ALPS, associated with heterozygous germline pathogenic variants in FAS), non-malignant lymphoproliferation typically manifests in the first years of life, inexplicably waxes and wanes, and then often decreases without treatment in the second decade of life; in many affected individuals, however, neither splenomegaly nor the overall expansion of lymphocyte subsets in peripheral blood decreases. Although autoimmunity is often not present at the time of diagnosis or at the time of the most extensive lymphoproliferation, autoantibodies can be detected before autoimmune disease manifests clinically. In ALPS-FAS caused by homozygous or compound heterozygous (biallelic) pathogenic variants in FAS, severe lymphoproliferation occurs before, at, or shortly after birth, and usually results in death at an early age. ALPS-sFAS, resulting from somatic FAS pathogenic variants in selected cell populations, notably the alpha/beta double-negative T cells (a/ß-DNT cells), appears to be similar to ALPS-FAS resulting from heterozygous germline pathogenic variants in FAS, although lower incidence of splenectomy and lower lymphocyte counts have been reported in ALPS-sFAS and no cases of lymphoma have yet been published.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:89007725
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
FAS
Variant:
c.*765T>C
rsID: rs9658776
Ref Allele: T
Alt Allele: C
Freq: 4.2447%uncommon
CADD: 5.041
ClinVar Submissions (1)
Autoimmune lymphoproliferative syndrome (ALPS), caused by defective lymphocyte homeostasis, is characterized by the following: Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age. Autoimmune disease, mostly directed toward blood cells. Lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma. In ALPS-FAS (the most common and best-characterized type of ALPS, associated with heterozygous germline pathogenic variants in FAS), non-malignant lymphoproliferation typically manifests in the first years of life, inexplicably waxes and wanes, and then often decreases without treatment in the second decade of life; in many affected individuals, however, neither splenomegaly nor the overall expansion of lymphocyte subsets in peripheral blood decreases. Although autoimmunity is often not present at the time of diagnosis or at the time of the most extensive lymphoproliferation, autoantibodies can be detected before autoimmune disease manifests clinically. In ALPS-FAS caused by homozygous or compound heterozygous (biallelic) pathogenic variants in FAS, severe lymphoproliferation occurs before, at, or shortly after birth, and usually results in death at an early age. ALPS-sFAS, resulting from somatic FAS pathogenic variants in selected cell populations, notably the alpha/beta double-negative T cells (a/ß-DNT cells), appears to be similar to ALPS-FAS resulting from heterozygous germline pathogenic variants in FAS, although lower incidence of splenectomy and lower lymphocyte counts have been reported in ALPS-sFAS and no cases of lymphoma have yet been published.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:89015215
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
LARS2
Variant:
c.-36G>A
rsID: rs75054661
Ref Allele: G
Alt Allele: A
Freq: 4.2471%uncommon
CADD: 0.152
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 02, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:45391634
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
OTOF
Variant:
c.2703G>A
(p.Ser901=)
rsID: rs4997760
Ref Allele: C
Alt Allele: T
Freq: 4.2614%uncommon
CADD: 0.018
ClinVar Submissions (3)
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:26476291
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:26476291
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
GHSR
Variant:
c.*1024G>C
rsID: rs9880206
Ref Allele: C
Alt Allele: G
Freq: 4.2814%uncommon
CADD: 0.025
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:172444137
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
TSC2
Variant:
c.976-63G>A
rsID: rs12927333
Ref Allele: G
Alt Allele: A
Freq: 4.2909%uncommon
CADD: 3.215
ClinVar Submissions (1)
Tuberous sclerosis complex (TSC) involves abnormalities of the skin (hypomelanotic macules, confetti skin lesions, facial angiofibromas, shagreen patches, fibrous cephalic plaques, ungual fibromas); brain (subependymal nodules, cortical dysplasias, and subependymal giant cell astrocytomas [SEGAs], seizures, intellectual disability / developmental delay, psychiatric illness); kidney (angiomyolipomas, cysts, renal cell carcinomas); heart (rhabdomyomas, arrhythmias); and lungs (lymphangioleiomyomatosis [LAM], multifocal micronodular pneumonocyte hyperplasia). Central nervous system tumors are the leading cause of morbidity and mortality; renal disease is the second leading cause of early death.
Last Evaluated: -
Review Status: no assertion provided
Number of Submitters: 1
Clinical Significance: not provided
Assembly: GRCh38
Chromosome/Position: 16:2060607
Hetero
Gene:
OTOF
Variant:
c.4677G>A
(p.Val1559=)
rsID: rs2272071
Ref Allele: C
Alt Allele: T
Freq: 4.3124%uncommon
CADD: 0.643
ClinVar Submissions (4)
OTOF-related deafness (DFNB9 nonsyndromic hearing loss) is characterized by two phenotypes: prelingual nonsyndromic hearing loss and, less frequently, temperature-sensitive nonsyndromic auditory neuropathy (TS-NSAN). The nonsyndromic hearing loss is bilateral severe-to-profound congenital deafness. In the first one or two years of life, OTOF-related deafness can appear to be an auditory neuropathy based on electrophysiologic testing in which auditory brain stem responses (ABRs) are absent and otoacoustic emissions (OAEs) are present. However, with time OAEs disappear and electrophysiologic testing is more consistent with a cochlear defect. The distinction between auditory neuropathy and a cochlear defect is important as cochlear implants may be of marginal value in persons with auditory neuropathy but have been shown to be effective for individuals with OTOF-related deafness. TS-NSAN is characterized by normal-to-mild hearing loss in the absence of fever and significant hearing loss ranging from severe to profound in the presence of fever. When the fever resolves, hearing returns to normal.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:26465794
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:26465794
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:26465794
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
PNP
Variant:
c.*1057T>C
rsID: rs60379427
Ref Allele: T
Alt Allele: C
Freq: 4.3196%uncommon
CADD: 4.667
ClinVar Submissions (1)
Purine nucleoside phosphorylase deficiency is a rare autosomal recessive immunodeficiency disorder characterized mainly by decreased T-cell function. Some patients also have neurologic impairment (review by Aust et al., 1992).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 14:20477658
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
TSC2
Variant:
c.3884-56C>G
rsID: rs1800724
Ref Allele: C
Alt Allele: G
Freq: 4.3212%uncommon
CADD: 4.672
ClinVar Submissions (1)
Tuberous sclerosis complex (TSC) involves abnormalities of the skin (hypomelanotic macules, confetti skin lesions, facial angiofibromas, shagreen patches, fibrous cephalic plaques, ungual fibromas); brain (subependymal nodules, cortical dysplasias, and subependymal giant cell astrocytomas [SEGAs], seizures, intellectual disability / developmental delay, psychiatric illness); kidney (angiomyolipomas, cysts, renal cell carcinomas); heart (rhabdomyomas, arrhythmias); and lungs (lymphangioleiomyomatosis [LAM], multifocal micronodular pneumonocyte hyperplasia). Central nervous system tumors are the leading cause of morbidity and mortality; renal disease is the second leading cause of early death.
Last Evaluated: -
Review Status: no assertion provided
Number of Submitters: 1
Clinical Significance: not provided
Assembly: GRCh38
Chromosome/Position: 16:2083639
Hetero
Gene:
TSC2
Variant:
c.1578C>T
(p.Ser526=)
rsID: rs34012042
Ref Allele: C
Alt Allele: T
Freq: 4.3283%uncommon
CADD: 6.021
ClinVar Submissions (9)
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Apr 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 9
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:2064406
Lymphangioleiomyomatosis (LAM) is a condition that affects the lungs, the kidneys, and the lymphatic system. The lymphatic system consists of a network of vessels that transport lymph fluid and immune cells throughout the body. Lymph fluid helps exchange immune cells, proteins, and other substances between the blood and tissues.LAM is found almost exclusively in women. It often occurs as a feature of an inherited syndrome called tuberous sclerosis complex. When LAM occurs alone it is called isolated or sporadic LAM.Signs and symptoms of LAM most often appear during a woman's thirties. Affected women have an overgrowth of abnormal smooth muscle-like cells (LAM cells) in the lungs, resulting in the formation of lung cysts and the destruction of normal lung tissue. They may also have an accumulation of fluid in the cavity around the lungs (chylothorax).The lung abnormalities resulting from LAM may cause difficulty breathing (dyspnea), chest pain, and coughing, which may bring up blood (hemoptysis). Many women with this disorder have recurrent episodes of collapsed lung (spontaneous pneumothorax). The lung problems may be progressive and, without lung transplantation, may eventually lead to limitations in activities of daily living, the need for oxygen therapy, and respiratory failure. Although LAM cells are not considered cancerous, they may spread between tissues (metastasize). As a result, the condition may recur even after lung transplantation.Women with LAM may develop cysts in the lymphatic vessels of the chest and abdomen. These cysts are called lymphangioleiomyomas. Affected women may also develop tumors called angiomyolipomas made up of LAM cells, fat cells, and blood vessels. Angiomyolipomas usually develop in the kidneys. Internal bleeding is a common complication of angiomyolipomas.
Last Evaluated: Apr 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 9
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:2064406
Lymphangioleiomyomatosis (LAM) is a condition that affects the lungs, the kidneys, and the lymphatic system. The lymphatic system consists of a network of vessels that transport lymph fluid and immune cells throughout the body. Lymph fluid helps exchange immune cells, proteins, and other substances between the blood and tissues.LAM is found almost exclusively in women. It often occurs as a feature of an inherited syndrome called tuberous sclerosis complex. When LAM occurs alone it is called isolated or sporadic LAM.Signs and symptoms of LAM most often appear during a woman's thirties. Affected women have an overgrowth of abnormal smooth muscle-like cells (LAM cells) in the lungs, resulting in the formation of lung cysts and the destruction of normal lung tissue. They may also have an accumulation of fluid in the cavity around the lungs (chylothorax).The lung abnormalities resulting from LAM may cause difficulty breathing (dyspnea), chest pain, and coughing, which may bring up blood (hemoptysis). Many women with this disorder have recurrent episodes of collapsed lung (spontaneous pneumothorax). The lung problems may be progressive and, without lung transplantation, may eventually lead to limitations in activities of daily living, the need for oxygen therapy, and respiratory failure. Although LAM cells are not considered cancerous, they may spread between tissues (metastasize). As a result, the condition may recur even after lung transplantation.Women with LAM may develop cysts in the lymphatic vessels of the chest and abdomen. These cysts are called lymphangioleiomyomas. Affected women may also develop tumors called angiomyolipomas made up of LAM cells, fat cells, and blood vessels. Angiomyolipomas usually develop in the kidneys. Internal bleeding is a common complication of angiomyolipomas.
Last Evaluated: Apr 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 9
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:2064406
Tuberous sclerosis complex (TSC) involves abnormalities of the skin (hypomelanotic macules, confetti skin lesions, facial angiofibromas, shagreen patches, fibrous cephalic plaques, ungual fibromas); brain (subependymal nodules, cortical dysplasias, and subependymal giant cell astrocytomas [SEGAs], seizures, intellectual disability / developmental delay, psychiatric illness); kidney (angiomyolipomas, cysts, renal cell carcinomas); heart (rhabdomyomas, arrhythmias); and lungs (lymphangioleiomyomatosis [LAM], multifocal micronodular pneumonocyte hyperplasia). Central nervous system tumors are the leading cause of morbidity and mortality; renal disease is the second leading cause of early death.
Last Evaluated: Apr 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 9
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:2064406
Tuberous sclerosis complex (TSC) involves abnormalities of the skin (hypomelanotic macules, confetti skin lesions, facial angiofibromas, shagreen patches, fibrous cephalic plaques, ungual fibromas); brain (subependymal nodules, cortical dysplasias, and subependymal giant cell astrocytomas [SEGAs], seizures, intellectual disability / developmental delay, psychiatric illness); kidney (angiomyolipomas, cysts, renal cell carcinomas); heart (rhabdomyomas, arrhythmias); and lungs (lymphangioleiomyomatosis [LAM], multifocal micronodular pneumonocyte hyperplasia). Central nervous system tumors are the leading cause of morbidity and mortality; renal disease is the second leading cause of early death.
Last Evaluated: Apr 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 9
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:2064406
Tuberous sclerosis complex (TSC) involves abnormalities of the skin (hypomelanotic macules, confetti skin lesions, facial angiofibromas, shagreen patches, fibrous cephalic plaques, ungual fibromas); brain (subependymal nodules, cortical dysplasias, and subependymal giant cell astrocytomas [SEGAs], seizures, intellectual disability / developmental delay, psychiatric illness); kidney (angiomyolipomas, cysts, renal cell carcinomas); heart (rhabdomyomas, arrhythmias); and lungs (lymphangioleiomyomatosis [LAM], multifocal micronodular pneumonocyte hyperplasia). Central nervous system tumors are the leading cause of morbidity and mortality; renal disease is the second leading cause of early death.
Last Evaluated: Apr 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 9
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:2064406
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Apr 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 9
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:2064406
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 9
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:2064406
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
TBX3
Variant:
c.*132G>A
rsID: rs79564336
Ref Allele: C
Alt Allele: T
Freq: 4.3833%uncommon
CADD: 3.582
ClinVar Submissions (1)
The ulnar-mammary syndrome is an autosomal dominant disorder characterized by posterior limb deficiencies or duplications, apocrine/mammary gland hypoplasia and/or dysfunction, abnormal dentition, delayed puberty in males, and genital anomalies (Bamshad et al., 1996).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:114671709
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
MYO6
Variant:
c.*1703C>T
rsID: rs9360957
Ref Allele: C
Alt Allele: T
Freq: 4.3928%uncommon
CADD: 0.583
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:75916715
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:75916715
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
MTHFR
Variant:
c.*3288C>T
rsID: rs3737967
Ref Allele: G
Alt Allele: A
Freq: 4.4231%uncommon
CADD: 2.049
ClinVar Submissions (1)
Neural tube defects have a birth incidence of approximately 1 in 1,000 in American Caucasians and are the second most common type of birth defect after congenital heart defects. The most common NTDs are open spina bifida (myelomeningocele) and anencephaly (206500) (Detrait et al., 2005). Women with elevated plasma homocysteine, low folate, or low vitamin B12 (cobalamin) are at increased risk of having a child with a neural tube defect (O'Leary et al., 2005). Motulsky (1996) cited evidence from the Centers for Disease Control ( Anonymous, 1992) that folic acid given before and during the first 4 weeks of pregnancy can prevent 50% or more of neural tube defects. Botto et al. (1999) and Detrait et al. (2005) provided reviews of neural tube defects. De Marco et al. (2006) provided a detailed review of neurulation and the possible etiologies of neural tube defects.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:11787392
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
MTHFR
Variant:
c.1781G>A
(p.Arg594Gln)
rsID: rs2274976
Ref Allele: C
Alt Allele: T
Freq: 4.4239%uncommon
CADD: 14.31
ClinVar Submissions (5)
Neural tube defects have a birth incidence of approximately 1 in 1,000 in American Caucasians and are the second most common type of birth defect after congenital heart defects. The most common NTDs are open spina bifida (myelomeningocele) and anencephaly (206500) (Detrait et al., 2005). Women with elevated plasma homocysteine, low folate, or low vitamin B12 (cobalamin) are at increased risk of having a child with a neural tube defect (O'Leary et al., 2005). Motulsky (1996) cited evidence from the Centers for Disease Control ( Anonymous, 1992) that folic acid given before and during the first 4 weeks of pregnancy can prevent 50% or more of neural tube defects. Botto et al. (1999) and Detrait et al. (2005) provided reviews of neural tube defects. De Marco et al. (2006) provided a detailed review of neurulation and the possible etiologies of neural tube defects.
Last Evaluated: Jan 13, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign, other
Assembly: GRCh38
Chromosome/Position: 1:11790870
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 13, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign, other
Assembly: GRCh38
Chromosome/Position: 1:11790870
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 13, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign, other
Assembly: GRCh38
Chromosome/Position: 1:11790870
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign, other
Hetero
Gene:
FANCA
Variant:
c.*986G>A
rsID: rs16966023
Ref Allele: C
Alt Allele: T
Freq: 4.4343%uncommon
CADD: 1.356
ClinVar Submissions (1)
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract – are more common in individuals with FA.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 16:89737615
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
CLDN14
Variant:
c.11C>T
(p.Thr4Met)
rsID: rs113831133
Ref Allele: G
Alt Allele: A
Freq: 4.439%uncommon
CADD: 15.54
ClinVar Submissions (5)
Last Evaluated: Dec 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 21:36461685
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 21:36461685
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
CDH3
Variant:
c.1430G>A
(p.Arg477His)
rsID: rs34494880
Ref Allele: G
Alt Allele: A
Freq: 4.4454%uncommon
CADD: 11.32
ClinVar Submissions (1)
Syndrome with the association of ectodermal dysplasia, ectrodactyly, and macular dystrophy. So far, it has been described in individuals from seven families. Hypotrichosis, dental anomalies and absent eyebrows have also been reported. Appears to be transmitted as an autosomal recessive trait and may be caused by mutations in the cadherin-3 gene (CH3, 16q22.1).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 16:68685210
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
SMAD4
Variant:
c.*6423G>C
rsID: rs2282544
Ref Allele: G
Alt Allele: C
Freq: 4.447%uncommon
CADD: 0.602
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 18:51084890
Myhre syndrome is a connective tissue disorder with multisystem involvement, progressive and proliferative fibrosis that may occur spontaneously or following trauma or surgery, mild-to-moderate intellectual disability, and in some instances, autistic-like behaviors. Organ systems primarily involved include: cardiovascular (congenital heart defects, long- and short-segment stenosis of the aorta and peripheral arteries, pericardial effusion, constrictive pericarditis, restrictive cardiomyopathy, and hypertension); respiratory (choanal stenosis, laryngotracheal narrowing, obstructive airway disease, or restrictive pulmonary disease), gastrointestinal (pyloric stenosis, duodenal strictures, severe constipation); and skin (thickened particularly on the hands and extensor surfaces). Additional findings include distinctive craniofacial features and skeletal involvement (intrauterine growth restriction, short stature, limited joint range of motion). To date, 55 individuals with molecularly confirmed Myhre syndrome have been reported.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 18:51084890
Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. The most common clinical manifestation is spontaneous and recurrent nosebleeds (epistaxis) beginning on average at age 12 years. Telangiectases (small AVMs) are most evident on the lips, tongue, buccal mucosa, face, chest, and fingers. The average age of onset is generally later than epistaxis, but may be during childhood. Large AVMs often cause symptoms when they occur in the lungs, liver, or brain; complications from bleeding or shunting may be sudden and catastrophic. Approximately 25% of individuals with HHT have GI bleeding, which most commonly begins after age 50 years.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 18:51084890
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Homo
Gene:
BIN1
Variant:
c.714C>T
(p.Tyr238=)
rsID: rs1137845
Ref Allele: G
Alt Allele: A
Freq: 4.4518%uncommon
CADD: 1
ClinVar Submissions (5)
Centronuclear myopathy is a condition characterized by muscle weakness (myopathy) and wasting (atrophy) in the skeletal muscles, which are the muscles used for movement. The severity of centronuclear myopathy varies among affected individuals, even among members of the same family.People with centronuclear myopathy begin experiencing muscle weakness at any time from birth to early adulthood. The muscle weakness slowly worsens over time and can lead to delayed development of motor skills, such as crawling or walking; muscle pain during exercise; and difficulty walking. Some affected individuals may need wheelchair assistance as the muscles atrophy and weakness becomes more severe. In rare instances, the muscle weakness improves over time.Some people with centronuclear myopathy experience mild to severe breathing problems related to the weakness of muscles needed for breathing. People with centronuclear myopathy may have droopy eyelids (ptosis) and weakness in other facial muscles, including the muscles that control eye movement. People with this condition may also have foot abnormalities, a high arch in the roof of the mouth (high-arched palate), and abnormal side-to-side curvature of the spine (scoliosis). Rarely, individuals with centronuclear myopathy have a weakened heart muscle (cardiomyopathy), disturbances in nerve function (neuropathy), or intellectual disability.A key feature of centronuclear myopathy is the displacement of the nucleus in muscle cells, which can be viewed under a microscope. Normally the nucleus is found at the edges of the rod-shaped muscle cells, but in people with centronuclear myopathy the nucleus is located in the center of these cells. How the change in location of the nucleus affects muscle cell function is unknown.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:127063631
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:127063631
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
EFHC1
Variant:
c.*392A>C
rsID: rs9463792
Ref Allele: A
Alt Allele: C
Freq: 4.4534%uncommon
CADD: 2.033
ClinVar Submissions (1)
Juvenile myoclonic epilepsy is a subtype of idiopathic generalized epilepsy (EIG; see 600669) affecting up to 26% of all individuals with EIG. Individuals with JME have afebrile seizures only, with onset in adolescence of myoclonic jerks. Myoclonic jerks occur usually in the morning (Janz and Durner, 1997). Genetic Heterogeneity of Juvenile Myoclonic Seizures Susceptibility to EJM can be conferred by variation in several other genes: EJM5 (611136), by variation in the GABRA1 gene (137160) on 5q34; EJM6 (see 607682), by variation in the CACNB4 gene (601949) on 2q23; EJM7 (see 613060), by variation in the GABRD gene (137163) on 1p36; EJM8 (see 607628), by variation in the CLCN2 gene (600570) on 3q27; and EJM10 (617924), by variation in the ICK gene (612325) on chromosome 6p12. In addition, EJM loci have been identified by linkage analysis: EJM2 (see 604827) on 15q14, EJM3 (608816) on 6p21, EJM4 (611364) on 5q12-q14, and EJM9 (614280) on 2q33-q36.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:52492733
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
PLCG2
Variant:
c.802C>T
(p.Arg268Trp)
rsID: rs1143687
Ref Allele: C
Alt Allele: T
Freq: 4.4566%uncommon
CADD: 25.6
ClinVar Submissions (2)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:81889208
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:81889208
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
KCNV2
Variant:
c.915G>A
(p.Val305=)
rsID: rs7859993
Ref Allele: G
Alt Allele: A
Freq: 4.4589%uncommon
CADD: 18.52
ClinVar Submissions (2)
Progressive cone dystrophy usually presents in childhood or early adult life, with many patients developing rod photoreceptor involvement in later life, thereby leading to considerable overlap between progressive cone dystrophy and cone-rod dystrophy. Both progressive cone dystrophy and cone-rod dystrophy have been associated with mutation in the GUCA1A gene (Michaelides et al., 2006). Intrafamilial variability in GUCA1A-associated macular disease ranges from mild photoreceptor degeneration to central areolar choroidal dystrophy (CACD), a form of retinal degeneration that primarily involves the macula and is characterized by a well-defined atrophic region of retinal pigment epithelium and choriocapillaris in the latest stage (Chen et al., 2017).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:2718654
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:2718654
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
-
Variant:
g.47678251C>A
rsID: rs17036817
Ref Allele: C
Alt Allele: A
Freq: 4.4709%uncommon
CADD: 0.567
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 19, 2013
Review Status: no assertion provided
Number of Submitters: 1
Clinical Significance: not provided
Assembly: GRCh38
Chromosome/Position: 2:47678251
Hetero
Gene:
WNK1
Variant:
c.-452G>A
rsID: rs118007973
Ref Allele: G
Alt Allele: A
Freq: 4.4852%uncommon
CADD: 14.61
ClinVar Submissions (1)
Hereditary sensory and autonomic neuropathy type II (HSAN2) is characterized by progressively reduced sensation to pain, temperature, and touch. Onset can be at birth and is often before puberty. The sensory deficit is predominantly distal with the lower limbs more severely affected than the upper limbs. Over time sensory function becomes severely reduced. Unnoticed injuries and neuropathic skin promote ulcerations and infections that result in spontaneous amputation of digits or the need for surgical amputation. Osteomyelitis is common. Painless fractures can complicate the disease. Autonomic disturbances are variable and can include hyperhidrosis, tonic pupils, and urinary incontinence in those with more advanced disease.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:753114
Pseudohypoaldosteronism type II (PHAII) is characterized by hyperkalemia despite normal glomerular filtration rate (GFR) and frequently by hypertension. Other associated findings in both children and adults include hyperchloremia, metabolic acidosis, and suppressed plasma renin levels. Aldosterone levels are variable, but are relatively low given the degree of hyperkalemia (elevated serum potassium is a potent stimulus for aldosterone secretion). Hypercalciuria is well described.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:753114
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
RFXANK
Variant:
c.144G>C
(p.Glu48Asp)
rsID: rs34282046
Ref Allele: G
Alt Allele: C
Freq: 4.494%uncommon
CADD: 9.293
ClinVar Submissions (2)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:19194090
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:19194090
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
PEX2
Variant:
c.*2377A>G
rsID: rs4388434
Ref Allele: T
Alt Allele: C
Freq: 4.5306%uncommon
CADD: 0.801
ClinVar Submissions (1)
Zellweger spectrum disorder (ZSD) is a phenotypic continuum ranging from severe to mild. While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term ZSD is now used to refer to all individuals with a PEX gene defect regardless of phenotype. Individuals with ZSD usually come to clinical attention in the newborn period or later in childhood. Affected newborns are hypotonic and feed poorly. They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling [chondrodysplasia punctata] of the patella[e] and other long bones), and liver disease which can be severe. Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress. Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss); neurologic involvement (ataxia, polyneuropathy, and leukodystrophy); liver dysfunction; adrenal insufficiency; and renal oxalate stones. While hypotonia and developmental delays are typical, intellect can be normal. Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 8:76980884
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
PEX2
Variant:
c.*727T>C
rsID: rs4610720
Ref Allele: A
Alt Allele: G
Freq: 4.5322%uncommon
CADD: 1.355
ClinVar Submissions (1)
Zellweger spectrum disorder (ZSD) is a phenotypic continuum ranging from severe to mild. While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term ZSD is now used to refer to all individuals with a PEX gene defect regardless of phenotype. Individuals with ZSD usually come to clinical attention in the newborn period or later in childhood. Affected newborns are hypotonic and feed poorly. They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling [chondrodysplasia punctata] of the patella[e] and other long bones), and liver disease which can be severe. Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress. Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss); neurologic involvement (ataxia, polyneuropathy, and leukodystrophy); liver dysfunction; adrenal insufficiency; and renal oxalate stones. While hypotonia and developmental delays are typical, intellect can be normal. Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 8:76982534
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
POLR3A;RPS24
Variant:
c.-109A>G
rsID: rs3740254
Ref Allele: A
Alt Allele: G
Freq: 4.5665%uncommon
CADD: 17.9
ClinVar Submissions (1)
Diamond-Blackfan anemia (DBA) in its classic form is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in up to 50% of affected individuals, and growth retardation in 30% of affected individuals. The hematologic complications occur in 90% of affected individuals during the first year of life. The phenotypic spectrum ranges from a mild form (e.g., mild anemia, no anemia with only subtle erythroid abnormalities, physical malformations without anemia) to a severe form of fetal anemia resulting in nonimmune hydrops fetalis. DBA is associated with an increased risk for acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors including osteogenic sarcoma.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:78033793
POLR3-related leukodystrophy, a hypomyelinating leukodystrophy with specific features on brain MRI, is characterized by varying combinations of four major clinical findings: Neurologic dysfunction, typically predominated by motor dysfunction (progressive cerebellar dysfunction, and to a lesser extent extrapyramidal [i.e., dystonia], pyramidal [i.e., spasticity] and cognitive dysfunctions). Abnormal dentition (delayed dentition, hypodontia, oligodontia, and abnormally placed or shaped teeth). Endocrine abnormalities such as short stature (in ~50% of individuals) with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as delayed, arrested, or absent puberty. Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe. POLR3-related leukodystrophy and 4H leukodystrophy are the two recognized terms for five previously described overlapping clinical phenotypes (initially described as distinct entities before their molecular basis was known). These include: Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); Ataxia, delayed dentition, and hypomyelination (ADDH); Tremor-ataxia with central hypomyelination (TACH); Leukodystrophy with oligodontia (LO); Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). Age of onset is typically in early childhood but later-onset cases have also been reported. An infant with Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) was recently reported to have pathogenic variants in POLR3A on exome sequencing. Confirmation of this as a very severe form of POLR3-related leukodystrophy awaits replication in other individuals with a clinical diagnosis of Wiedemann-Rautenstrauch syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:78033793
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
DUOX2
Variant:
c.2102G>A
(p.Arg701Gln)
rsID: rs113400262
Ref Allele: C
Alt Allele: T
Freq: 4.5744%uncommon
CADD: 13.46
ClinVar Submissions (2)
Congenital hypothyroidism is a partial or complete loss of function of the thyroid gland (hypothyroidism) that affects infants from birth (congenital). The thyroid gland is a butterfly-shaped tissue in the lower neck. It makes iodine-containing hormones that play an important role in regulating growth, brain development, and the rate of chemical reactions in the body (metabolism). People with congenital hypothyroidism have lower-than-normal levels of these important hormones.Congenital hypothyroidism occurs when the thyroid gland fails to develop or function properly. In 80 to 85 percent of cases, the thyroid gland is absent, severely reduced in size (hypoplastic), or abnormally located. These cases are classified as thyroid dysgenesis. In the remainder of cases, a normal-sized or enlarged thyroid gland (goiter) is present, but production of thyroid hormones is decreased or absent. Most of these cases occur when one of several steps in the hormone synthesis process is impaired; these cases are classified as thyroid dyshormonogenesis. Less commonly, reduction or absence of thyroid hormone production is caused by impaired stimulation of the production process (which is normally done by a structure at the base of the brain called the pituitary gland), even though the process itself is unimpaired. These cases are classified as central (or pituitary) hypothyroidism.Signs and symptoms of congenital hypothyroidism result from the shortage of thyroid hormones. Affected babies may show no features of the condition, although some babies with congenital hypothyroidism are less active and sleep more than normal. They may have difficulty feeding and experience constipation. If untreated, congenital hypothyroidism can lead to intellectual disability and slow growth. In the United States and many other countries, all hospitals test newborns for congenital hypothyroidism. If treatment begins in the first two weeks after birth, infants usually develop normally.Congenital hypothyroidism can also occur as part of syndromes that affect other organs and tissues in the body. These forms of the condition are described as syndromic. Some common forms of syndromic hypothyroidism include Pendred syndrome, Bamforth-Lazarus syndrome, and brain-lung-thyroid syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 15:45106171
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 15:45106171
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
TRAP1
Variant:
c.1032C>T
(p.Tyr344=)
rsID: rs11541712
Ref Allele: G
Alt Allele: A
Freq: 4.5943%uncommon
CADD: 0.029
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 23, 2016
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:3674351
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
MFN2
Variant:
c.*1100A>G
rsID: rs41278638
Ref Allele: A
Alt Allele: G
Freq: 4.6302%uncommon
CADD: 8.387
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:12012665
A group of slowly progressive inherited disorders affecting motor and sensory peripheral nerves. Subtypes include HMSNs I-VII. HMSN I and II both refer to CHARCOT-MARIE-TOOTH DISEASE. HMSN III refers to hypertrophic neuropathy of infancy. HMSN IV refers to REFSUM DISEASE. HMSN V refers to a condition marked by a hereditary motor and sensory neuropathy associated with spastic paraplegia (see SPASTIC PARAPLEGIA, HEREDITARY). HMSN VI refers to HMSN associated with an inherited optic atrophy (OPTIC ATROPHIES, HEREDITARY), and HMSN VII refers to HMSN associated with retinitis pigmentosa. (From Adams et al., Principles of Neurology, 6th ed, p1343)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:12012665
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
TBX3
Variant:
c.*747G>A
rsID: rs3741695
Ref Allele: C
Alt Allele: T
Freq: 4.6716%uncommon
CADD: 2.725
ClinVar Submissions (1)
The ulnar-mammary syndrome is an autosomal dominant disorder characterized by posterior limb deficiencies or duplications, apocrine/mammary gland hypoplasia and/or dysfunction, abnormal dentition, delayed puberty in males, and genital anomalies (Bamshad et al., 1996).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:114671094
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
EFHC1
Variant:
c.-195A>G
rsID: rs2296196
Ref Allele: A
Alt Allele: G
Freq: 4.6748%uncommon
CADD: 7.915
ClinVar Submissions (1)
Juvenile myoclonic epilepsy is a subtype of idiopathic generalized epilepsy (EIG; see 600669) affecting up to 26% of all individuals with EIG. Individuals with JME have afebrile seizures only, with onset in adolescence of myoclonic jerks. Myoclonic jerks occur usually in the morning (Janz and Durner, 1997). Genetic Heterogeneity of Juvenile Myoclonic Seizures Susceptibility to EJM can be conferred by variation in several other genes: EJM5 (611136), by variation in the GABRA1 gene (137160) on 5q34; EJM6 (see 607682), by variation in the CACNB4 gene (601949) on 2q23; EJM7 (see 613060), by variation in the GABRD gene (137163) on 1p36; EJM8 (see 607628), by variation in the CLCN2 gene (600570) on 3q27; and EJM10 (617924), by variation in the ICK gene (612325) on chromosome 6p12. In addition, EJM loci have been identified by linkage analysis: EJM2 (see 604827) on 15q14, EJM3 (608816) on 6p21, EJM4 (611364) on 5q12-q14, and EJM9 (614280) on 2q33-q36.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:52420216
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
PKD1
Variant:
c.12409C>T
(p.Leu4137=)
rsID: rs79899502
Ref Allele: G
Alt Allele: A
Freq: 4.6803%uncommon
CADD: 20.5
ClinVar Submissions (4)
Autosomal dominant polycystic kidney disease (ADPKD) is generally a late-onset multisystem disorder characterized by bilateral renal cysts, liver cysts, and an increased risk of intracranial aneurysms. Other manifestations include: cysts in the pancreas, seminal vesicles, and arachnoid membrane; dilatation of the aortic root and dissection of the thoracic aorta; mitral valve prolapse; and abdominal wall hernias. Renal manifestations include hypertension, renal pain, and renal insufficiency. Approximately 50% of individuals with ADPKD have end-stage renal disease (ESRD) by age 60 years. The prevalence of liver cysts increases with age and occasionally results in clinically significant severe polycystic liver disease (PLD). Overall the prevalence of intracranial aneurysms is fivefold higher than in the general population and further increased in those with a positive family history of aneurysms or subarachnoid hemorrhage. There is substantial variability in the severity of renal disease and other extrarenal manifestations even within the same family.
Last Evaluated: May 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:2090320
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:2090320
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:2090320
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
CAVIN4
Variant:
c.570A>T
(p.Ser190=)
rsID: rs28623148
Ref Allele: A
Alt Allele: T
Freq: 4.6891%uncommon
CADD: 17.82
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 23, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:100585926
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
ENPP1
Variant:
c.*1299C>T
rsID: rs11965061
Ref Allele: C
Alt Allele: T
Freq: 4.6907%uncommon
CADD: 0.206
ClinVar Submissions (1)
Generalized arterial calcification of infancy (GACI) is characterized by infantile onset of widespread arterial calcification and/or narrowing of large- and medium-sized vessels resulting in cardiovascular findings (which can include heart failure, respiratory distress, edema, cyanosis, hypertension, and/or cardiomegaly). Additional findings can include extravascular calcifications (particularly periarticular), typical skin and retinal manifestations of pseudoxanthoma elasticum (PXE), hearing loss, and development of rickets after infancy. While mortality in infancy is high, survival into the second and third decade has been reported.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:131891810
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:131891810
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
BIN1
Variant:
c.1573-18G>C
rsID: rs12466912
Ref Allele: C
Alt Allele: G
Freq: 4.6979%uncommon
CADD: 0.554
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 18, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:127050540
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
FANCI
Variant:
c.164C>T
(p.Pro55Leu)
rsID: rs62020347
Ref Allele: C
Alt Allele: T
Freq: 4.7034%uncommon
CADD: 25.2
ClinVar Submissions (4)
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract – are more common in individuals with FA.
Last Evaluated: Jan 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 15:89260719
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 15:89260719
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Low clinical importance, Likely benign — Probably benign.
Benign/Likely benign
Hetero
Gene:
EGR2
Variant:
c.1086A>C
(p.Arg362=)
rsID: rs45602133
Ref Allele: T
Alt Allele: G
Freq: 4.7186%uncommon
CADD: 17.65
ClinVar Submissions (3)
Charcot-Marie-Tooth disease encompasses a group of disorders called hereditary sensory and motor neuropathies that damage the peripheral nerves. Peripheral nerves connect the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound. Damage to the peripheral nerves that worsens over time can result in alteration or loss of sensation and wasting (atrophy) of muscles in the feet, legs, and hands.Charcot-Marie-Tooth disease usually becomes apparent in adolescence or early adulthood, but onset may occur anytime from early childhood through late adulthood. Symptoms of Charcot-Marie-Tooth disease vary in severity and age of onset even among members of the same family. Some people never realize they have the disorder because their symptoms are so mild, but most have a moderate amount of physical disability. A small percentage of people experience severe weakness or other problems which, in very rare cases, can be life-threatening. In most affected individuals, however, Charcot-Marie-Tooth disease does not affect life expectancy.Typically, the earliest symptoms of Charcot-Marie-Tooth disease result from muscle atrophy in the feet. Affected individuals may have foot abnormalities such as high arches (pes cavus), flat feet (pes planus), or curled toes (hammer toes). They often have difficulty flexing the foot or walking on the heel of the foot. These difficulties may cause a higher than normal step (steppage gait) and increase the risk of ankle injuries and tripping. As the disease worsens, muscles in the lower legs usually weaken, but leg and foot problems rarely require the use of a wheelchair.Affected individuals may also develop weakness in the hands, causing difficulty with daily activities such as writing, fastening buttons, and turning doorknobs. People with Charcot-Marie-Tooth disease typically experience a decreased sensitivity to touch, heat, and cold in the feet and lower legs, but occasionally feel aching or burning sensations. In rare cases, affected individuals have loss of vision or gradual hearing loss that sometimes leads to deafness.There are several types of Charcot-Marie-Tooth disease, which are differentiated by their effects on nerve cells and patterns of inheritance. Type 1 (CMT1) is characterized by abnormalities in myelin, the fatty substance that covers nerve cells, protecting them and helping to transmit nerve impulses. These abnormalities slow the transmission of nerve impulses and can affect the health of the nerve fiber. Type 2 (CMT2) is characterized by abnormalities in the fiber, or axon, that extends from a nerve cell body to muscles or to sense organs. These abnormalities reduce the strength of the nerve impulse. In forms of Charcot-Marie-Tooth disease classified as intermediate type, the nerve impulses are both slowed and reduced in strength, probably due to abnormalities in both myelin and axons. Type 4 (CMT4) is distinguished from the other types by its pattern of inheritance; it can affect either the axons or the myelin. Type X Charcot-Marie-Tooth disease (CMTX) is caused by mutations in genes on the X chromosome, one of the two sex chromosomes. Within the various types of Charcot-Marie-Tooth disease, subtypes (such as CMT1A, CMT1B, CMT2A, CMT4A, and CMTX1) indicate different genetic causes.Sometimes other, historical names are used to refer to particular forms of Charcot-Marie-Tooth disease. For example, Roussy-Levy syndrome is a form of CMT11 with the additional feature of rhythmic shaking (tremors). Dejerine-Sottas syndrome is a term sometimes used to describe a severe, early childhood form of Charcot-Marie-Tooth disease; it is also sometimes called type 3 (CMT3). Depending on the specific gene that is altered, this severe, early-onset form of the disorder may also be classified as CMT1 or CMT4. CMTX5 is also known as Rosenberg-Chutorian syndrome.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:62813552
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:62813552
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
COL18A1
Variant:
c.2490G>A
(p.Pro830=)
rsID: rs61731167
Ref Allele: G
Alt Allele: A
Freq: 4.752%uncommon
CADD: 0.029
ClinVar Submissions (2)
Knobloch syndrome is an autosomal recessive developmental disorder primarily characterized by typical eye abnormalities, including high myopia, cataracts, dislocated lens, vitreoretinal degeneration, and retinal detachment, with occipital skull defects, which can range from occipital encephalocele to occult cutis aplasia (summary by Aldahmesh et al., 2011).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 21:45489512
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 21:45489512
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
ABCA4
Variant:
c.635G>A
(p.Arg212His)
rsID: rs6657239
Ref Allele: C
Alt Allele: T
Freq: 4.7648%uncommon
CADD: 24.4
ClinVar Submissions (6)
Last Evaluated: May 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:94098927
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells of the macula lutea.
Last Evaluated: May 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:94098927
Last Evaluated: May 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:94098927
Last Evaluated: May 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:94098927
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:94098927
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:94098927
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Insufficiently evaluated not reviewed — This variant has been associated with AMD.
Benign/Likely benign
Hetero
Gene:
PKD1
Variant:
c.12176C>T
(p.Ala4059Val)
rsID: rs3209986
Ref Allele: G
Alt Allele: A
Freq: 4.7687%uncommon
CADD: 10.68
ClinVar Submissions (4)
Autosomal dominant polycystic kidney disease (ADPKD) is generally a late-onset multisystem disorder characterized by bilateral renal cysts, liver cysts, and an increased risk of intracranial aneurysms. Other manifestations include: cysts in the pancreas, seminal vesicles, and arachnoid membrane; dilatation of the aortic root and dissection of the thoracic aorta; mitral valve prolapse; and abdominal wall hernias. Renal manifestations include hypertension, renal pain, and renal insufficiency. Approximately 50% of individuals with ADPKD have end-stage renal disease (ESRD) by age 60 years. The prevalence of liver cysts increases with age and occasionally results in clinically significant severe polycystic liver disease (PLD). Overall the prevalence of intracranial aneurysms is fivefold higher than in the general population and further increased in those with a positive family history of aneurysms or subarachnoid hemorrhage. There is substantial variability in the severity of renal disease and other extrarenal manifestations even within the same family.
Last Evaluated: May 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:2090553
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:2090553
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:2090553
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Low clinical importance, Likely benign — Probably benign.
Benign
Hetero
Gene:
ABCB11
Variant:
c.270T>C
(p.Phe90=)
rsID: rs4148777
Ref Allele: A
Alt Allele: G
Freq: 4.7719%uncommon
CADD: 16.81
ClinVar Submissions (3)
Progressive familial intrahepatic cholestasis (PFIC) is a disorder that causes progressive liver disease, which typically leads to liver failure. In people with PFIC, liver cells are less able to secrete a digestive fluid called bile. The buildup of bile in liver cells causes liver disease in affected individuals.Signs and symptoms of PFIC typically begin in infancy and are related to bile buildup and liver disease. Specifically, affected individuals experience severe itching, yellowing of the skin and whites of the eyes (jaundice), failure to gain weight and grow at the expected rate (failure to thrive), high blood pressure in the vein that supplies blood to the liver (portal hypertension), and an enlarged liver and spleen (hepatosplenomegaly).There are three known types of PFIC: PFIC1, PFIC2, and PFIC3. The types are also sometimes described as shortages of particular proteins needed for normal liver function. Each type has a different genetic cause.In addition to signs and symptoms related to liver disease, people with PFIC1 may have short stature, deafness, diarrhea, inflammation of the pancreas (pancreatitis), and low levels of fat-soluble vitamins (vitamins A, D, E, and K) in the blood. Affected individuals typically develop liver failure before adulthood.The signs and symptoms of PFIC2 are typically related to liver disease only; however, these signs and symptoms tend to be more severe than those experienced by people with PFIC1. People with PFIC2 often develop liver failure within the first few years of life. Additionally, affected individuals are at increased risk of developing a type of liver cancer called hepatocellular carcinoma.Most people with PFIC3 have signs and symptoms related to liver disease only. Signs and symptoms of PFIC3 usually do not appear until later in infancy or early childhood; rarely, people are diagnosed in early adulthood. Liver failure can occur in childhood or adulthood in people with PFIC3.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:169013391
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:169013391
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
C12orf65
Variant:
c.*354G>A
rsID: rs11057214
Ref Allele: G
Alt Allele: A
Freq: 4.7799%uncommon
CADD: 0.084
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 12:123257385
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
CTNNA3
Variant:
c.1872C>A
(p.Val624=)
rsID: rs10997034
Ref Allele: G
Alt Allele: T
Freq: 4.7886%uncommon
CADD: 6.356
ClinVar Submissions (2)
Arrhythmogenic right ventricular cardiomyopathy/dysplasia is characterized by progressive fibrofatty myocardial replacement, primarily of the right ventricle. The main clinical features are structural and functional abnormalities of the ventricles, electrocardiographic depolarization/repolarization changes, reentrant arrhythmias, and sudden death (summary by van Hengel et al., 2013).
Last Evaluated: Oct 26, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:66280482
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 26, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:66280482
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
GHSR
Variant:
c.*792G>C
rsID: rs9880652
Ref Allele: C
Alt Allele: G
Freq: 4.8022%uncommon
CADD: 0.021
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:172444369
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
PRICKLE1
Variant:
c.-181G>A
rsID: rs117521428
Ref Allele: C
Alt Allele: T
Freq: 4.8054%uncommon
CADD: 8.977
ClinVar Submissions (1)
PRICKLE1-related progressive myoclonus epilepsy (PME) with ataxia is characterized by myoclonic seizures (lightning-like jerks), generalized convulsive seizures, varying degrees of neurologic decline especially manifest as ataxia, and normal intellectual abilities. Onset of symptoms is between ages five and ten years. Action myoclonus may affect the limbs or bulbar muscles, sometimes with spontaneous myoclonus of facial muscles. Marked dysarthria may occur. Seizures can be myoclonic or tonic-clonic and are often nocturnal.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 12:42589597
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
ACTN2
Variant:
c.*700A>G
rsID: rs12733179
Ref Allele: A
Alt Allele: G
Freq: 4.8189%uncommon
CADD: 2.619
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:236763319
A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:236763319
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
DDOST;PINK1;PINK1-AS
Variant:
c.*457A>C
rsID: rs150466875
Ref Allele: T
Alt Allele: G
Freq: 4.8285%uncommon
CADD: 5.179
ClinVar Submissions (1)
A genetically heterogeneous group of heritable disorders resulting from defects in protein N-glycosylation.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:20651922
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:20651922
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
SH3BP2
Variant:
c.357+15G>T
rsID: rs62620003
Ref Allele: G
Alt Allele: T
Freq: 4.8348%uncommon
CADD: 9.69
ClinVar Submissions (2)
Cherubism is a childhood-onset, autoinflammatory bone disease characterized by bilateral and symmetric proliferative fibroosseous lesions limited to the mandible and maxilla. The enlargement is usually symmetric in nature. The phenotype ranges from no clinical manifestations to severe mandibular and maxillary overgrowth with respiratory, vision, speech, and swallowing problems. In most affected persons, teeth are displaced, unerupted, unformed, or absent, or may appear to be floating in cystlike spaces; malocclusion, premature exfoliation of deciduous teeth, and root resorption have also been reported. The course and duration of the active process of bone destruction varies between affected individuals; the onset is usually in early childhood, and typically new lesions can occur until puberty. Regression of the lesions occurs as they become filled with bone and remodel during the second and third decade of life. By age 30 years, the facial abnormalities associated with cherubism are not usually recognizable and residual deformity of the jaws is rare. Typically, cherubism is an isolated benign condition; the affected person has normal intellectual skills and is without other physical anomalies.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:2824745
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:2824745
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
KCNV2
Variant:
c.978C>T
(p.Asp326=)
rsID: rs7860945
Ref Allele: C
Alt Allele: T
Freq: 4.8547%uncommon
CADD: 16.76
ClinVar Submissions (2)
Progressive cone dystrophy usually presents in childhood or early adult life, with many patients developing rod photoreceptor involvement in later life, thereby leading to considerable overlap between progressive cone dystrophy and cone-rod dystrophy. Both progressive cone dystrophy and cone-rod dystrophy have been associated with mutation in the GUCA1A gene (Michaelides et al., 2006). Intrafamilial variability in GUCA1A-associated macular disease ranges from mild photoreceptor degeneration to central areolar choroidal dystrophy (CACD), a form of retinal degeneration that primarily involves the macula and is characterized by a well-defined atrophic region of retinal pigment epithelium and choriocapillaris in the latest stage (Chen et al., 2017).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:2718717
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:2718717
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero
Gene:
ROBO3
Variant:
c.1824C>T
(p.Gly608=)
rsID: rs77513537
Ref Allele: C
Alt Allele: T
Freq: 4.8715%uncommon
CADD: 1.742
ClinVar Submissions (1)
HGPPS is an autosomal recessive neurologic disorder characterized by eye movement abnormalities apparent from birth and childhood-onset progressive scoliosis. These features are associated with a developmental malformation of the brainstem including hypoplasia of the pons and cerebellar peduncles and defective decussation of certain neuronal systems. Cognitive function is normal (summary by Bosley et al., 2005). Genetic Heterogeneity of Familial Horizontal Gaze Palsy With Progressive Scoliosis See also HGPPS2 (617542), caused by mutation in the DCC gene (120470) on chromosome 18q21.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:124874109
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
TP63
Variant:
c.*435C>T
rsID: rs78233713
Ref Allele: C
Alt Allele: T
Freq: 4.877%uncommon
CADD: 1.25
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:189894937
A condition in which middle parts of the hands and/or feet (digits and meta-carpals and -tarsals) are missing giving a cleft appearance. The severity is very variable ranging from slightly hypoplastic 3rd toe/fingers over absent 2nd or 3rd toes/fingers as far as oligo- or monodactyl hands and/or feet.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:189894937
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:189894937
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
COL5A1
Variant:
c.4447-45G>A
rsID: rs3811147
Ref Allele: G
Alt Allele: A
Freq: 4.8778%uncommon
CADD: 4.524
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:134820071
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
TGIF1
Variant:
c.488C>T
(p.Pro163Leu)
rsID: rs2229333
Ref Allele: C
Alt Allele: T
Freq: 4.8826%uncommon
CADD: 24.3
ClinVar Submissions (3)
Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having "microform" HPE.
Last Evaluated: Mar 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 18:3457609
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 18:3457609
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Homo
Gene:
EGF
Variant:
c.2073A>G
(p.Ala691=)
rsID: rs2302135
Ref Allele: A
Alt Allele: G
Freq: 4.9009%uncommon
CADD: 1.168
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:109979991
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
AMACR;C1QTNF3-AMACR;SLC45A2
Variant:
c.*617G>T
rsID: rs12659370
Ref Allele: C
Alt Allele: A
Freq: 4.9216%uncommon
CADD: 2.896
ClinVar Submissions (1)
AMACR deficiency is a rare autosomal recessive peroxisomal disorder characterized by adult onset of variable neurodegenerative symptoms affecting the central and peripheral nervous systems. Features may include seizures, visual failure, sensorimotor neuropathy, spasticity, migraine, and white matter hyperintensities on brain imaging. Serum pristanic acid and C27 bile acid intermediates are increased (summary by Smith et al., 2010).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:33988476
Oculocutaneous albinism is a group of conditions that affect coloring (pigmentation) of the skin, hair, and eyes. Affected individuals typically have very fair skin and white or light-colored hair. Long-term sun exposure greatly increases the risk of skin damage and skin cancers, including an aggressive form of skin cancer called melanoma, in people with this condition. Oculocutaneous albinism also reduces pigmentation of the colored part of the eye (the iris) and the light-sensitive tissue at the back of the eye (the retina). People with this condition usually have vision problems such as reduced sharpness; rapid, involuntary eye movements (nystagmus); and increased sensitivity to light (photophobia).Researchers have identified multiple types of oculocutaneous albinism, which are distinguished by their specific skin, hair, and eye color changes and by their genetic cause. Oculocutaneous albinism type 1 is characterized by white hair, very pale skin, and light-colored irises. Type 2 is typically less severe than type 1; the skin is usually a creamy white color and hair may be light yellow, blond, or light brown. Type 3 includes a form of albinism called rufous oculocutaneous albinism, which usually affects dark-skinned people. Affected individuals have reddish-brown skin, ginger or red hair, and hazel or brown irises. Type 3 is often associated with milder vision abnormalities than the other forms of oculocutaneous albinism. Type 4 has signs and symptoms similar to those seen with type 2.Several additional types of this disorder have been proposed, each affecting one or a few families.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:33988476
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
GAN
Variant:
c.*1388A>G
rsID: rs41484544
Ref Allele: A
Alt Allele: G
Freq: 4.9288%uncommon
CADD: 13.36
ClinVar Submissions (1)
Giant axonal neuropathy (GAN) is an early-onset fatal neurodegenerative disorder. GAN starts as severe peripheral motor and sensory neuropathy during infancy and evolves into central nervous system impairment (intellectual disability, seizures, cerebellar signs, and pyramidal tract signs). Most individuals become wheelchair dependent in the second decade of life and eventually bedridden with severe polyneuropathy, ataxia, and dementia. Death usually occurs in the third decade.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 16:81378984
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
GAN
Variant:
c.*1068T>G
rsID: rs57170812
Ref Allele: T
Alt Allele: G
Freq: 4.932%uncommon
CADD: 9.393
ClinVar Submissions (1)
Giant axonal neuropathy (GAN) is an early-onset fatal neurodegenerative disorder. GAN starts as severe peripheral motor and sensory neuropathy during infancy and evolves into central nervous system impairment (intellectual disability, seizures, cerebellar signs, and pyramidal tract signs). Most individuals become wheelchair dependent in the second decade of life and eventually bedridden with severe polyneuropathy, ataxia, and dementia. Death usually occurs in the third decade.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 16:81378664
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
GAN
Variant:
c.*1658T>G
rsID: rs16955221
Ref Allele: T
Alt Allele: G
Freq: 4.9344%uncommon
CADD: 1.895
ClinVar Submissions (1)
Giant axonal neuropathy (GAN) is an early-onset fatal neurodegenerative disorder. GAN starts as severe peripheral motor and sensory neuropathy during infancy and evolves into central nervous system impairment (intellectual disability, seizures, cerebellar signs, and pyramidal tract signs). Most individuals become wheelchair dependent in the second decade of life and eventually bedridden with severe polyneuropathy, ataxia, and dementia. Death usually occurs in the third decade.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 16:81379254
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
GAN
Variant:
c.*1250T>G
rsID: rs61096092
Ref Allele: T
Alt Allele: G
Freq: 4.9487%uncommon
CADD: 0.453
ClinVar Submissions (1)
Giant axonal neuropathy (GAN) is an early-onset fatal neurodegenerative disorder. GAN starts as severe peripheral motor and sensory neuropathy during infancy and evolves into central nervous system impairment (intellectual disability, seizures, cerebellar signs, and pyramidal tract signs). Most individuals become wheelchair dependent in the second decade of life and eventually bedridden with severe polyneuropathy, ataxia, and dementia. Death usually occurs in the third decade.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 16:81378846
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Likely benign
Hetero
Gene:
PKHD1
Variant:
c.8302+18A>G
rsID: rs12529717
Ref Allele: T
Alt Allele: C
Freq: 4.9615%uncommon
CADD: 0.317
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 04, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:51830843
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
PLAU
Variant:
c.691A>C
(p.Lys231Gln)
rsID: rs2227567
Ref Allele: A
Alt Allele: C
Freq: 4.9822%uncommon
CADD: 1.66
ClinVar Submissions (1)
Quebec platelet disorder is an autosomal dominant bleeding disorder due to a gain-of-function defect in fibrinolysis. Although affected individuals do not exhibit systemic fibrinolysis, they show delayed onset bleeding after challenge, such as surgery. The hallmark of the disorder is markedly increased PLAU levels within platelets, which causes intraplatelet plasmin generation and secondary degradation of alpha-granule proteins. The disorder shows a favorable therapeutic response to fibrinolytic inhibitors (summary by Diamandis et al., 2009).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:73913990
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign
Hetero
Gene:
MFN2
Variant:
c.1569C>T
(p.Ser523=)
rsID: rs1042837
Ref Allele: C
Alt Allele: T
Freq: 4.9854%uncommon
CADD: 12.42
ClinVar Submissions (3)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:12005784
A group of slowly progressive inherited disorders affecting motor and sensory peripheral nerves. Subtypes include HMSNs I-VII. HMSN I and II both refer to CHARCOT-MARIE-TOOTH DISEASE. HMSN III refers to hypertrophic neuropathy of infancy. HMSN IV refers to REFSUM DISEASE. HMSN V refers to a condition marked by a hereditary motor and sensory neuropathy associated with spastic paraplegia (see SPASTIC PARAPLEGIA, HEREDITARY). HMSN VI refers to HMSN associated with an inherited optic atrophy (OPTIC ATROPHIES, HEREDITARY), and HMSN VII refers to HMSN associated with retinitis pigmentosa. (From Adams et al., Principles of Neurology, 6th ed, p1343)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:12005784
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:12005784
This variant has been classified as benign. Any further interpretation or conclusions drawn should be approached with caution.
Benign/Likely benign
Hetero