ClinVar Miner

Submissions for variant NM_000722.4(CACNA2D1):c.1375G>C (p.Val459Leu)

gnomAD frequency: 0.00009  dbSNP: rs765696205
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485553 SCV000574002 uncertain significance not provided 2017-03-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CACNA2D1 gene. The V459L variant has not been published as pathogenic or been reported as benign to our knowledge. Additionally, this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the V459L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.
Labcorp Genetics (formerly Invitae), Labcorp RCV001306235 SCV001495596 uncertain significance Brugada syndrome 2024-04-08 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 459 of the CACNA2D1 protein (p.Val459Leu). This variant is present in population databases (rs765696205, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CACNA2D1-related conditions. ClinVar contains an entry for this variant (Variation ID: 424214). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Ambry Genetics RCV002383935 SCV002696401 uncertain significance Cardiovascular phenotype 2024-03-13 criteria provided, single submitter clinical testing The p.V459L variant (also known as c.1375G>C), located in coding exon 16 of the CACNA2D1 gene, results from a G to C substitution at nucleotide position 1375. The valine at codon 459 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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