ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.91A>G (p.Asn31Asp) (rs531598856)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170816 SCV000223371 uncertain significance not provided 2013-04-24 criteria provided, single submitter clinical testing p.Asn31Asp (AAT>GAT): c.91 A>G in exon 2 of the CACNA1C gene (NM_000719.6). The Asn31Asp variant in the CACNA1C gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Asn31Asp was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Asn31Asp variant results in a semi-conservative amino acid substitution of a neutral Asparagine with a negatively-charged Aspartic acid at a position that is conserved across species. However, in silico analysis predicts Asn31Asp is benign to the protein structure/function. Mutations in nearby residues have not been reported, indicating this region of the protein may tolerate change. With the clinical and molecular information available at this time, we cannot definitively determine if Asn31Asp is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s).
Invitae RCV000229376 SCV000285606 uncertain significance Long QT syndrome 2017-03-06 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 31 of the CACNA1C protein (p.Asn31Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs531598856, ExAC 0.03%) but has not been reported in the literature in individuals with a CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 190678). 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 is a rare missense change that is not predicted to affect protein function or cause disease. However, the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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