ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.376C>T (p.His126Tyr)

dbSNP: rs879253995
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236069 SCV000293099 uncertain significance not provided 2023-02-16 criteria provided, single submitter clinical testing Observed in multiple unrelated individuals with Charcot-Marie-Tooth disease (Panosyan et al., 2017; Verhelst et al., 2000; Volodarsky et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28768847, 11030070, 32376792)
Labcorp Genetics (formerly Invitae), Labcorp RCV000698707 SCV000827387 likely pathogenic Charcot-Marie-Tooth Neuropathy X 2023-10-22 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 126 of the GJB1 protein (p.His126Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 11030070, 28768847, 32376792). ClinVar contains an entry for this variant (Variation ID: 245904). 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 not expected to disrupt GJB1 protein function. 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 RCV000789056 SCV000928405 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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