ClinVar Miner

Submissions for variant NM_000722.4(CACNA2D1):c.2333C>T (p.Ser778Leu) (rs202108848)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000245597 SCV000320564 uncertain significance Cardiovascular phenotype 2015-12-01 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);Insufficient or conflicting evidence;In silico models in agreement (benign)
GeneDx RCV000484301 SCV000571995 uncertain significance not provided 2017-08-14 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CACNA2D1 gene. The S778L variant has not been published as pathogenic or been reported as benign to our knowledge. 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). The S778L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis suggests that this variant is probably damaging to the protein structure/function. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Invitae RCV000536261 SCV000636986 uncertain significance Brugada syndrome 2019-02-01 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 778 of the CACNA2D1 protein (p.Ser778Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs202108848, ExAC 0.01%) but has not been reported in the literature in individuals with a CACNA2D1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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