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

gnomAD frequency: 0.00002  dbSNP: rs752247655

Total submissions: 4

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	2020-03-05	criteria provided, single submitter	clinical testing	The p.I1142L variant (also known as c.3424A>C), located in coding exon 27 of the CACNA1C gene, results from an A to C substitution at nucleotide position 3424. The isoleucine at codon 1142 is replaced by leucine, an amino acid with highly similar properties. This variant was reported in an arrhythmia cohort; however, clinical details were limited (Adler A et al. Circ Arrhythm Electrophysiol, 2016 Jan;9:e003440). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631563	SCV000752645	uncertain significance	Long QT syndrome	2022-10-18	criteria provided, single submitter	clinical testing	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. 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 expected to disrupt CACNA1C protein function. ClinVar contains an entry for this variant (Variation ID: 190659). This missense change has been observed in individual(s) with an unspecified cardiac condition (PMID: 26743238). This variant is present in population databases (rs752247655, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1142 of the CACNA1C protein (p.Ile1142Leu).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.