ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.3862G>A (p.Ala1288Thr) (rs367895193)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000719972 SCV000850846 uncertain significance History of neurodevelopmental disorder 2017-04-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000170802 SCV000223357 uncertain significance not provided 2017-01-17 criteria provided, single submitter clinical testing The A1288T variant of uncertain significance in the CACNA1C gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. A1288T was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and was not observed with any significant frequency in the Exome Aggregation Consortium, indicating it is not a common benign variant in these populations. The A1288T 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. Moreover, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, 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.
Illumina Clinical Services Laboratory,Illumina RCV000295765 SCV000377844 uncertain significance Brugada syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000324911 SCV000377845 uncertain significance Timothy syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000474210 SCV000553012 uncertain significance Long QT syndrome 2016-11-13 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1288 of the CACNA1C protein (p.Ala1288Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs367895193, ExAC 0.04%) but has not been reported in the literature in individuals with a CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 190664). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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