ClinVar Miner

Submissions for variant NM_000720.4(CACNA1D):c.1127C>T (p.Ala376Val)

gnomAD frequency: 0.00004  dbSNP: rs759274321
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
King Laboratory, University of Washington RCV000454162 SCV001976373 likely pathogenic Sinoatrial node dysfunction and deafness 2020-08-01 criteria provided, single submitter research CACNA1D c.1127C>T, p.A376V alters a completely conserved residue in a transmembrane domain of CACNA1D. The variant is homozygous in 6 children from 4 Palestinian families with a syndromic phenotype including moderate pre-lingual hearing loss and cardiac signs (Abu Rayyan 2020). It is absent from 1300 Palestinian controls and present in 4/251488 alleles on gnomAD, all in heterozygotes.
Labcorp Genetics (formerly Invitae), Labcorp RCV001861652 SCV002220630 uncertain significance not provided 2024-03-30 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 376 of the CACNA1D protein (p.Ala376Val). This variant is present in population databases (rs759274321, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of autosomal recessive CACNA1D-related conditions (PMID: 30498240, 32747562; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 402284). 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 CACNA1D protein function with a negative predictive value of 80%. 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.
Hereditary Research Laboratory, Bethlehem University RCV000454162 SCV000538131 pathogenic Sinoatrial node dysfunction and deafness 2016-06-04 no assertion criteria provided research congenital, moderate
University of Washington Center for Mendelian Genomics, University of Washington RCV000454162 SCV001480019 likely pathogenic Sinoatrial node dysfunction and deafness no assertion criteria provided research

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