ClinVar Miner

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

gnomAD frequency: 0.00008  dbSNP: 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 2024-08-19 criteria provided, single submitter clinical testing The c.2333C>T (p.S778L) alteration is located in exon 29 (coding exon 29) of the CACNA2D1 gene. This alteration results from a C to T substitution at nucleotide position 2333, causing the serine (S) at amino acid position 778 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000536261 SCV000636986 uncertain significance Brugada syndrome 2024-07-19 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 778 of the CACNA2D1 protein (p.Ser778Leu). This variant is present in population databases (rs202108848, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of CACNA2D1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 264556). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.

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