ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.3424A>C (p.Ile1142Leu) (rs752247655)

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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 RCV000619014 SCV000736176 uncertain significance Cardiovascular phenotype 2017-12-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000170797 SCV000223352 uncertain significance not provided 2018-01-12 criteria provided, single submitter clinical testing The Ile1142Leu variant in the CACNA1C gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Although the Ile1142Leu results in a conservative substitution of one non-polar amino acid for another, the Ile1142 residue is conserved across species. In silico analysis predicts Ile1142Leu is possibly damaging to the proteins structure/function (Adzhubei I et al., 2010). The NHLBI ESP Exome Variant Server reports Ile1142Leu was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. However, Ile1142Leu occurs in a region of the CACNA1C gene with few reported mutations suggesting this region of the protein may tolerate change. With the clinical and molecular information available at this time, we cannot determine whether Ile1142Leu in the CACNA1C gene is a disease-causing mutation or benign variant.
Invitae RCV000631563 SCV000752645 uncertain significance Long QT syndrome 2017-09-07 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with leucine at codon 1142 of the CACNA1C protein (p.Ile1142Leu). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is present in population databases (rs752247655, ExAC 0.002%). This variant has been reported in an individual affected with an unspecified cardiac condition (PMID: 26743238). ClinVar contains an entry for this variant (Variation ID: 190659). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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