ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.77C>G (p.Ser26Trp) (rs587777876)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000535675 SCV000658921 pathogenic Charcot-Marie-Tooth Neuropathy X 2019-10-11 criteria provided, single submitter clinical testing This sequence change replaces serine with tryptophan at codon 26 of the GJB1 protein (p.Ser26Trp). The serine residue is highly conserved and there is a large physicochemical difference between serine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with X-linked Charcot-Marie-Tooth disease in 4 related families and is considered a founder mutation in French-Canadian population (PMID: 11252295). This variant has also been reported in an individual affected with severe Charcot-Marie-Tooth disease (PMID: 11437164). Experimental studies have shown that this missense change alters channel gating but does not significantly alter channel conductance (PMID: 25969535). A different missense substitution at this codon (p.Ser26Leu) has been determined to be pathogenic (PMID: 8990008, 25429913, 9354338, 25802885). This suggests that the serine residue is critical for GJB1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Inherited Neuropathy Consortium RCV000789319 SCV000928672 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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