ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.231G>A (p.Trp77Ter) (rs879254096)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235279 SCV000293447 pathogenic not provided 2016-03-28 criteria provided, single submitter clinical testing The W77X nonsense variant in the GJB1 gene has been reported previously in association with CMTX1 (Bone et al., 1997; Numakura et al., 2002). This pathogenic variant is predicted to cause loss of normal protein function through protein truncation, as the last 207 amino acids are lost. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, multiple other downstream nonsense and loss-of-function variants have been reported in the Human Gene Mutation Database in association with CMTX1 (Stenson et al., 2014).
Invitae RCV001388434 SCV001589431 pathogenic Charcot-Marie-Tooth Neuropathy X 2020-08-26 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the GJB1 gene (p.Trp77*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 207 amino acids of the GJB1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 12402337). ClinVar contains an entry for this variant (Variation ID: 246095). This variant disrupts the C-terminus of the GJB1 protein. Other variant(s) that disrupt this region (p.Arg220*) have been determined to be pathogenic (PMID: 7477983, 8162049, 9364054, 21291455). 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.
Inherited Neuropathy Consortium RCV000789171 SCV000928523 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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