ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.1703C>T (p.Thr568Met)

gnomAD frequency: 0.00001  dbSNP: rs749561588
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170782 SCV000223337 uncertain significance not provided 2012-08-07 criteria provided, single submitter clinical testing p.Thr568Met (ACG>ATG):c.1703 C>T in exon 13 of the CACNA1C gene (NM_000719.6). The Thr568Met variant in the CACNA1C gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Thr568Met results in a semi-conservative amino acid substitution of a polar Threonine residue with a non-polar Methionine residue at a position that is conserved across species. The NHLBI ESP Exome Variant Server reports Thr568Met was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in nearby codons have been reported in association with LQTS, indicating this region of the protein may be tolerant of change. With the clinical and molecular information available at this time, we cannot definitively determine if Thr568Met is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s).
Fulgent Genetics, Fulgent Genetics RCV002478533 SCV002782528 uncertain significance Timothy syndrome; Brugada syndrome 3; Long qt syndrome 8 2021-08-20 criteria provided, single submitter clinical testing
Invitae RCV002517637 SCV002947245 uncertain significance Long QT syndrome 2022-01-01 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 568 of the CACNA1C protein (p.Thr568Met). ClinVar contains an entry for this variant (Variation ID: 190644). 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. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0").

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