ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.1864G>A (p.Val622Ile) (rs768270021)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170784 SCV000223339 uncertain significance not provided 2019-01-11 criteria provided, single submitter clinical testing The Val622Ile variant in the CACNA1C gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Val622Ile results in a conservative amino acid substitution of one non-polar amino acid for another, this substitution occurs at a position that is conserved across species. However, there have been no nearby mutations reported in association with LQTS/Timothy syndrome, indicating this region of the protein may be tolerant of change. Nevertheless, Val622Ile was absent from the 1000 Genomes database, and the NHLBI ESP Exome Variant Server reports Val622Ile was not observed in approximately 6000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. One in silico analysis program predicts Val622Ile is possibly damaging to the protein structure/function, while another predicts it is tolerated. With the clinical and molecular information available at this time, we cannot definitively determine if Val622Ile is a disease-causing mutation or a rare benign variant.
Ambry Genetics RCV000619791 SCV000737943 uncertain significance Cardiovascular phenotype 2017-03-15 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000805998 SCV000945976 uncertain significance Long QT syndrome 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 622 of the CACNA1C protein (p.Val622Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs768270021, ExAC 0.005%). This variant has not been reported in the literature in individuals with CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 190646). 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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