ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.4942G>A (p.Ala1648Thr) (rs370432385)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724254 SCV000230504 uncertain significance not provided 2014-11-18 criteria provided, single submitter clinical testing
GeneDx RCV000178426 SCV000535948 uncertain significance not specified 2017-01-10 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CACNA1C gene. The A1648T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. A1648T was not observed with any significant frequency in the NHLBI Exome Sequencing Project or in the Exome Aggregation Consortium, indicating it is not a common benign variant in these populations. The A1648T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, where T1648 is the native residue in multiple species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, no pathogenic missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014), indicating that this region of the gene is not known to harbor disease-causing variants.
Invitae RCV000468918 SCV000553017 uncertain significance Long QT syndrome 2017-04-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1648 of the CACNA1C protein (p.Ala1648Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs370432385, ExAC 0.02%). This variant has been reported in an individual who died without explanation (PMID: 27930701). This variant is also known as c.5086G>A, p.A1696T in the literature. ClinVar contains an entry for this variant (Variation ID: 197406). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000522719 SCV000616613 uncertain significance Timothy syndrome 2017-04-13 criteria provided, single submitter clinical testing

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