ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.179G>A (p.Cys60Tyr) (rs1555937082)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000654836 SCV000776738 likely pathogenic Charcot-Marie-Tooth Neuropathy X 2017-09-27 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 60 of the GJB1 protein (p.Cys60Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. 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 a single family (PMID: 25043634). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Cys60Phe) has been determined to be pathogenic (PMID: 8162049, 8816997, 9452099, 10093067). This suggests that the cysteine residue is critical for GJB1 protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Inherited Neuropathy Consortium RCV000789055 SCV000928404 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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