ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.460G>A (p.Ala154Thr) (rs1064796583)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483676 SCV000573423 uncertain significance not provided 2017-02-16 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CACNA1C gene. The A154T variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A154T 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. This substitution occurs at a position where only amino acids with similar properties to Alanine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Ambry Genetics RCV000718884 SCV000849748 uncertain significance History of neurodevelopmental disorder 2017-05-31 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV001047449 SCV001211411 uncertain significance Long QT syndrome 2019-01-31 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 154 of the CACNA1C protein (p.Ala154Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 423695). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly 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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