ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.2327A>G (p.Lys776Arg)

gnomAD frequency: 0.00004  dbSNP: rs786205751
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170787 SCV000223342 uncertain significance not provided 2021-02-08 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV000701597 SCV000830407 uncertain significance Long QT syndrome 2022-10-14 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 776 of the CACNA1C protein (p.Lys776Arg). This variant is present in population databases (rs786205751, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 190649). 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 CACNA1C protein function. 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 RCV002453576 SCV002736909 uncertain significance Cardiovascular phenotype 2020-03-23 criteria provided, single submitter clinical testing The p.K776R variant (also known as c.2327A>G), located in coding exon 16 of the CACNA1C gene, results from an A to G substitution at nucleotide position 2327. The lysine at codon 776 is replaced by arginine, 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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