ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.187G>A (p.Val63Ile) (rs116840818)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000217618 SCV000278980 pathogenic not provided 2018-05-23 criteria provided, single submitter clinical testing The V63I missense variant in the GJB1 gene has been reported previously in association with CMTX1 (Fairweather et al., 1994; Hoyer et al., 2014) and is associated with a mild to moderate clinical presentation in both males and females (Deschenes et al., 1997). Functional studies in murine cells demonstrate that at least some of the V63I variant protein is able to localize to the cell surface, show no significant effect on the ability of the mutant protein to form gap junctions, and to date have failed to elucidate the pathogenic mechanism of the V63I mutant protein (Deschenes et al., 1997; Wang et al., 2003). 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. In addition, this substitution occurs at a position that is highly conserved across species and many other missense variants are reported in this region of the protein (Stenson et al., 2014). Therefore the presence of the V63I pathogenic variant is consistent with a diagnosis of CMTX1
Athena Diagnostics Inc RCV000217618 SCV000613479 pathogenic not provided 2016-03-30 criteria provided, single submitter clinical testing
Invitae RCV001064548 SCV001229458 pathogenic Charcot-Marie-Tooth Neuropathy X 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 63 of the GJB1 protein (p.Val63Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals and a family affected with Charcot-Marie-Tooth disease (PMID: 8162049, 12542510, 10093067). ClinVar contains an entry for this variant (Variation ID: 21081). This variant has been reported to mildly affect GJB1 protein function (PMID: 9364054, 11393532, 15006706). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000217618 SCV001245762 pathogenic not provided 2017-02-01 criteria provided, single submitter clinical testing
GeneReviews RCV000020171 SCV000040500 pathologic Charcot-Marie-Tooth Neuropathy X Type 1 2010-04-15 no assertion criteria provided curation Converted during submission to Pathogenic.
Inherited Neuropathy Consortium RCV000789665 SCV000929039 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only
Natera, Inc. RCV000789665 SCV001462643 pathogenic Charcot-Marie-Tooth disease 2020-09-16 no assertion criteria provided clinical testing

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