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

dbSNP: rs116840818

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000217618	SCV000278980	pathogenic	not provided	2025-03-17	criteria provided, single submitter	clinical testing	Reported previously in association with CMTX1 (PMID: 8162049, 25025039) and is associated with a mild to moderate clinical presentation in both males and females (PMID: 9364054); Functional studies in murine cells demonstrate that at least some of the V63I variant protein is able to localize to the cell surface, shows 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 (PMID: 9364054, 15006706); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 10093067, 30569560, 15006706, 20301548, 9099841, 12477701, 9633821, 12542510, 11393532, 17100997, 25025039, 9361298, 32376792, 37284795, 8162049, 9364054)
Athena Diagnostics	RCV000217618	SCV000613479	pathogenic	not provided	2016-03-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001064548	SCV001229458	pathogenic	Charcot-Marie-Tooth Neuropathy X	2024-07-24	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 63 of the GJB1 protein (p.Val63Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 8162049, 10093067, 12542510). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21081). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJB1 protein function. Experimental studies have shown that this missense change affects GJB1 function (PMID: 9364054, 11393532, 15006706). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000217618	SCV001245762	pathogenic	not provided	2017-02-01	criteria provided, single submitter	clinical testing
GeneReviews	RCV000020171	SCV000040500	not provided	Charcot-Marie-Tooth disease X-linked dominant 1		no assertion provided	literature only
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
Clinical Genetics, Academic Medical Center	RCV000217618	SCV001924182	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000217618	SCV001955069	pathogenic	not provided		no assertion criteria provided	clinical testing
Inherited Neuropathy Consortium Ii, University Of Miami	RCV000020171	SCV004174730	uncertain significance	Charcot-Marie-Tooth disease X-linked dominant 1	2016-01-06	no assertion criteria provided	literature only