ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.1A>G (p.Met1Val)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Concord Molecular Medicine Laboratory, Concord Repatriation General Hospital RCV003129589 SCV004100878 likely pathogenic Charcot-Marie-Tooth disease X-linked dominant 1 2023-11-05 criteria provided, single submitter clinical testing The missense variant in the first coding position, c.1A>G, in GJB1 predicts a “start loss” as coding effect and affects the translation initiation codon, p.(Met1?). This variant is absent in control population (gnomAD). It has not been reported in literature, but a hemizygous c.1A>T start loss change has been described to cause CMTX1 (PMID: 24627108). Other missense variants at the same protein position have been reported as pathogenic (PMID: 24958482, 25771809, 27844031). Functional studies showed that the start codon mutation caused loss of protein (PMID: 25771809). In silico analysis suggests this variant to be damaging (REVEL: 0.972). The current evidence allows a classification of the variant as “likely pathogenic” (ACMG criteria: PP3_strong, PVS1_moderate, PM2_supporting).
Invitae RCV003581890 SCV004264152 pathogenic Charcot-Marie-Tooth Neuropathy X 2024-01-31 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the GJB1 mRNA. The next in-frame methionine is located at codon 34. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with GJB1-related conditions (PMID: 20039784, 24958582, 25771809; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2431056). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects GJB1 function (PMID: 25771809). For these reasons, this variant has been classified as Pathogenic.
Inherited Neuropathy Consortium Ii, University Of Miami RCV003129589 SCV003806283 pathogenic Charcot-Marie-Tooth disease X-linked dominant 1 2020-01-07 no assertion criteria provided clinical testing

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