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 2020-02-17 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect as R215W prevents the formation of functional channels (Omori et al., 1996; Castro et al., 1999).; Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in nearby residues reported in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 10234007, 11835375, 8816997, 8162049, 11571214, 32376792)
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 2020-02-05 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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