ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.630_631GT[1] (p.Cys211fs) (rs587783646)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000146026 SCV000193180 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
Counsyl RCV000169500 SCV000220961 likely pathogenic Deafness, autosomal recessive 1A 2014-12-17 criteria provided, single submitter literature only
GeneDx RCV000497843 SCV000589635 pathogenic not provided 2017-06-09 criteria provided, single submitter clinical testing The c.632_633delGT variant in the GJB2 gene has been reported previously in trans with the c.167delT variant in an individual with sensorineural hearing loss (Kelley et al., 1998). The c.632_633delGT variant causes a frameshift starting with codon Cysteine 211, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Cys211LeufsX5. This variant is predicted to cause loss of normal protein function through protein truncation. The c.632_633delGT variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.632_633delGT as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000497843 SCV000700814 pathogenic not provided 2016-12-06 criteria provided, single submitter clinical testing
Invitae RCV000497843 SCV001388056 pathogenic not provided 2019-07-11 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the GJB2 gene (p.Cys211Leufs*5). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acids of the GJB2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another GJB2 in individual(s) with nonsyndromic sensorineural hearing loss (PMID: 9529365, 12910486). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 631 632del in the literature. ClinVar contains an entry for this variant (Variation ID: 158608). This variant has been reported to affect GJB2 protein function (PMID: 20863150). For these reasons, this variant has been classified as Pathogenic.
Natera, Inc. RCV000169500 SCV001463359 pathogenic Deafness, autosomal recessive 1A 2020-09-16 no assertion criteria provided clinical testing

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