ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.502T>G (p.Cys168Gly)

dbSNP: rs1057518780
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000415205 SCV000492920 likely pathogenic Decreased nerve conduction velocity; Sensory neuropathy; Pes cavus; Hammertoe; Distal muscle weakness 2014-11-27 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001199043 SCV001370038 likely pathogenic Charcot-Marie-Tooth disease X-linked dominant 1 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PM5,PP3,PP5.
Labcorp Genetics (formerly Invitae), Labcorp RCV005090683 SCV005748902 uncertain significance Charcot-Marie-Tooth Neuropathy X 2024-04-30 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 168 of the GJB1 protein (p.Cys168Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GJB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 373934). 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 with a positive predictive value of 80%. This variant disrupts the p.Cys168 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in individuals with GJB1-related conditions (PMID: 12325071, 15241803), 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000414760 SCV000492569 likely pathogenic Pes cavus; Peroneal muscle atrophy; Distal lower limb muscle weakness; Hand muscle atrophy 2016-08-10 no assertion criteria provided clinical testing

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