ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000619014 SCV000736176 uncertain significance Cardiovascular phenotype 2017-12-15 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000631563 SCV000752645 uncertain significance Long QT syndrome 2019-10-03 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.
Integrated Genetics/Laboratory Corporation of America RCV001192664 SCV001360923 uncertain significance not specified 2019-12-24 criteria provided, single submitter clinical testing Variant summary: CACNA1C c.3424A>C (p.Ile1142Leu) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250964 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3424A>C has been reported in the literature in one individual who may be affected by Arrhythmia (Adler_2016). The report does not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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