ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.399G>T (p.Trp133Cys) (rs1602349302)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001053372 SCV001217630 uncertain significance Charcot-Marie-Tooth Neuropathy X 2019-10-11 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 133 of the GJB1 protein (p.Trp133Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Charcot-Marie-Tooth disease (PMID: 9452099). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant disrupts the p.Trp133 amino acid residue in GJB1. Other variant(s) that disrupt this residue (p.Trp133Arg) have been observed in individuals with GJB1-related conditions (PMID: 7477983), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Inherited Neuropathy Consortium RCV000789945 SCV000929330 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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