ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.72G>C (p.Trp24Cys)

dbSNP: rs1602348658
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Genetics Laboratory, London Health Sciences Centre RCV001173557 SCV001336651 likely pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Invitae RCV002559664 SCV003215303 likely pathogenic Charcot-Marie-Tooth Neuropathy X 2022-11-29 criteria provided, single submitter clinical testing 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. This variant disrupts the p.Trp24 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in individuals with GJB1-related conditions (PMID: 23011429), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB1 protein function. ClinVar contains an entry for this variant (Variation ID: 917092). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 12185164; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 24 of the GJB1 protein (p.Trp24Cys).

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