ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.1342G>A (p.Asp448Asn) (rs786205746)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170772 SCV000223327 uncertain significance not provided 2013-05-31 criteria provided, single submitter clinical testing p.Asp448Asn (GAT>AAT): c.1342 G>A in exon 9 of the CACNA1C gene (NM_000719.6). The Asp448Asn variant in the CACNA1C gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Asp448Asn results in a non-conservative amino acid substitution of a negatively charged Aspartic acid with a neutral, polar Asparagine at a position that is conserved across species. In silico analysis predicts Asp448Asn is probably damaging to the protein structure/function. The Asp448Asn variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in nearby residues have been reported in association with LQTS, indicating this region of the protein may be tolerant of change.With the clinical and molecular information available at this time, we cannot definitively determine if Asp448Asn is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s).
Invitae RCV000553290 SCV000627507 uncertain significance Long QT syndrome 2017-06-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 448 of the CACNA1C protein (p.Asp448Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 190635). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on CACNA1C function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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