ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.643C>T (p.Arg215Trp) (rs879254099)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236009 SCV000293451 pathogenic not provided 2016-04-26 criteria provided, single submitter clinical testing The R215W pathogenic variant has been reported previously in association with CMTX1(Fairweather et al., 1994; Dubourg et al., 2001) and functional studies show that R215W prevents theformation of functional channels (Omori et al., 1996; Castro et al., 1999). The R215W variant wasnot observed in approximately 6,500 individuals of European and African American ancestry,indicating that it is not a common benign variant in these populations. The R215W variant is anon-conservative amino acid substitution, which is likely to impact secondary protein structure asthese residues differ in polarity, charge, size and/or other properties. In silico analysis predicts thisvariant is probably damaging to the protein structure/function. This substitution occurs at a positionwhere amino acids with properties similar to Arginine are tolerated across species and several missensevariants in nearby residues have been reported in the Inherited Peripheral Neuropathy (IPN) databaseand Human Gene Mutation Database in association with CMTX1 (Stenson et al., 2014). Therefore,the presence of the R215W pathogenic variant is consistent with a diagnosis of CMTX1
Athena Diagnostics Inc RCV000236009 SCV000613497 pathogenic not provided 2016-11-18 criteria provided, single submitter clinical testing
Invitae RCV000688999 SCV000816633 pathogenic Charcot-Marie-Tooth Neuropathy X 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 215 of the GJB1 protein (p.Arg215Trp). The arginine residue is moderately 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 many individuals and families affected with Charcot-Marie-Tooth disease, type 1X (CMT1X) (PMID: 8162049, 25947624, 11571214, 11835375, 27098783, 8698335, 9187667, 16912585, 22464564) and has been reported to segregate with CMT1X in an affected family (PMID: 8162049). This variant has also been reported in an affected individual with a CMT2 phenotype (PMID: 11437164). ClinVar contains an entry for this variant (Variation ID: 246098). Experimental studies have shown that this missense change adversely affects protein function in vitro (PMID: 8816997, 10234007). For these reasons, this variant has been classified as Pathogenic.
Inherited Neuropathy Consortium RCV000789850 SCV000929235 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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