ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.43C>T (p.Arg15Trp) (rs116840815)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000167902 SCV000218550 pathogenic Charcot-Marie-Tooth Neuropathy X 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 15 of the GJB1 protein (p.Arg15Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with CMT (PMID: 9600589, 11835375, 21149811), and it has been observed to segregate with disease in multiple families (PMID: 9099841, 9328258, 10521546). ClinVar contains an entry for this variant (Variation ID: 21084). Experimental studies in model systems have shown that this mutation impacts the function of the GJB1-encoded protein product (connexin 32) (PMID: 11325342, 22771394). In summary, this variant is a missense change that has been shown to segregate with disease and affect GJB1 protein function. For these reasons, it has been classified as Pathogenic.
GeneDx RCV000236824 SCV000292871 pathogenic not provided 2018-09-07 criteria provided, single submitter clinical testing The R15W mutation has been previously reported in association with Charcot-Marie-Tooth neuropathy (Wicklein et al., 1997), and functional studies show that the R15W mutation significantly alters the channel function (Abrams et al., 2001). Additionally, a different amino acid substitution at the same position (R15Q) and other missense mutations in nearby residues (V13L/M, N14S, H16L/P/Q) have been reported in the Human Gene Mutation Database in association with Charcot-Marie-Tooth neuropathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. R15W 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.
Athena Diagnostics Inc RCV000236824 SCV000613486 pathogenic not provided 2016-08-24 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,London Health Sciences Centre RCV000789234 SCV001336650 pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
GeneReviews RCV000020174 SCV000040505 pathologic Charcot-Marie-Tooth Neuropathy X Type 1 2010-04-15 no assertion criteria provided curation Converted during submission to Pathogenic.
Inherited Neuropathy Consortium RCV000789234 SCV000928586 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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