ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.173C>G (p.Pro58Arg)

dbSNP: rs1602348876
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mayo Clinic Laboratories, Mayo Clinic RCV003480816 SCV004225667 uncertain significance not provided 2022-07-05 criteria provided, single submitter clinical testing PP1, PP3, PM2
Labcorp Genetics (formerly Invitae), Labcorp RCV003581713 SCV004299609 likely pathogenic Charcot-Marie-Tooth Neuropathy X 2023-02-13 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 58 of the GJB1 protein (p.Pro58Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Charcot-Marie-Tooth disease (PMID: 9633821; Invitae). ClinVar contains an entry for this variant (Variation ID: 637239). 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. This variant disrupts the p.Pro58Ser amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23773993). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 RCV000789310 SCV000928663 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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