ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.238C>T (p.Gln80Ter) (rs199883710)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000412105 SCV000487417 likely pathogenic Deafness, autosomal recessive 1A 2016-09-09 criteria provided, single submitter clinical testing
Counsyl RCV000410120 SCV000487418 likely pathogenic Deafness, autosomal dominant 3a 2016-09-09 criteria provided, single submitter clinical testing
Invitae RCV001054602 SCV001218946 pathogenic not provided 2019-11-20 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the GJB2 gene (p.Gln80*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 147 amino acids of the GJB2 protein. This variant is present in population databases (rs199883710, ExAC 0.01%). This variant has been observed in individuals affected with hearing loss (PMID: 17041943, 30168495). ClinVar contains an entry for this variant (Variation ID: 371685). This variant disrupts the C-terminus of the GJB2 protein. Other variant(s) that disrupt this region (p.His100Argfs*14) have been determined to be pathogenic (PMID: 22991996, 26043044, 24341454, 10633133, 12111646, 27610647, 20083784). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192518 SCV001360715 pathogenic Nonsyndromic Deafness 2019-07-18 criteria provided, single submitter clinical testing Variant summary: GJB2 c.238C>T (p.Gln80X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8e-06 in 251380 control chromosomes (gnomAD). c.238C>T has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss (Putcha_2007, Singh_2018, Tang_2006). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV001054602 SCV001873542 likely pathogenic not provided 2021-06-18 criteria provided, single submitter clinical testing Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 147 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 24077912, 27535533, 17041943, 17666888, 30473554, 30168495, 16950989, 25087612)

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