ClinVar Miner

Submissions for variant NM_000165.5(GJA1):c.119C>T (p.Ala40Val)

dbSNP: rs1554200992
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000504313 SCV000594980 pathogenic Oculodentodigital dysplasia 2016-01-28 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002506224 SCV002813787 pathogenic Autosomal dominant palmoplantar keratoderma and congenital alopecia; Atrioventricular septal defect and common atrioventricular junction; Craniometaphyseal dysplasia, autosomal recessive; Hypoplastic left heart syndrome 1; Oculodentodigital dysplasia, autosomal recessive; Syndactyly type 3; Oculodentodigital dysplasia; Erythrokeratodermia variabilis et progressiva 3 2021-07-09 criteria provided, single submitter clinical testing
Invitae RCV002524189 SCV003440010 pathogenic Oculodentodigital dysplasia, autosomal recessive 2023-12-06 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 40 of the GJA1 protein (p.Ala40Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant oculodentodigital dysplasia (PMID: 12457340, 25327171, 30628995). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 435323). 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 GJA1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GJA1 function (PMID: 15879313). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV003228939 SCV003926448 pathogenic not provided 2023-05-16 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect showing compromised channel function and a complete lack of functional electrical coupling (Shibayama et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16418219, 16378922, 34094714, 12457340, 32224865, 25327171, 30628995, 15879313)

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