ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.1555G>A (p.Ala519Thr) (rs371702432)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619866 SCV000737897 uncertain significance Cardiovascular phenotype 2017-02-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000424636 SCV000535608 uncertain significance not provided 2018-10-22 criteria provided, single submitter clinical testing The A519T 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. A519T was not observed with any significant frequency in the NHLBI Exome Sequencing Project or the Exome Aggregation Consortium (ExAC), indicating it is not a common benign variant in these populations. The A519T 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.Nevertheless, additional evidence is needed to determine whether this variant is pathogenic or benign. This result cannot be used for diagnosis or family member screening at this time.
Invitae RCV000813437 SCV000953797 uncertain significance Long QT syndrome 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 519 of the CACNA1C protein (p.Ala519Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs371702432, ExAC 0.01%). This variant has been observed in an individual affected with sudden unexplained death, however that individual also had several other possibly causative genetic variants identified (PMID: 28704380). ClinVar contains an entry for this variant (Variation ID: 392350). 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: "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.

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