ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.1485C>A (p.His495Gln) (rs373335068)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170777 SCV000223332 uncertain significance not provided 2018-04-25 criteria provided, single submitter clinical testing p.His495Gln (CAC>CAA): c.1485 C>A in exon 11 of the CACNA1C gene (NM_000719.6). The His495Gln variant in the CACNA1C gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. His495Gln results in a non-conservative amino acid substitution of a positively charged Histidine with a neutral, polar Glutamine at a position that is conserved across species. The His495Gln variant was not observed at any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Nevertheless, no mutations in nearby residues have been reported in association with arrhythmia. In silico analysis predicts His495Gln is benign to the protein structure/function. With the clinical and molecular information available at this time, we cannot definitively determine if His495Gln is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s).
Invitae RCV000631680 SCV000752763 uncertain significance Long QT syndrome 2019-09-03 criteria provided, single submitter clinical testing This sequence change replaces histidine with glutamine at codon 495 of the CACNA1C protein (p.His495Gln). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and glutamine. This variant is present in population databases (rs373335068, ExAC 0.05%). This variant has not been reported in the literature in individuals with CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 190639). 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 and their clinical significance is uncertain. 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.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000656158 SCV000678352 uncertain significance Wolff-Parkinson-White pattern 2017-07-14 no assertion criteria provided research This variant was identified in an individual with Wolff-Parkinson-White syndrome

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