CACNA1C encodes for the alpha-1c subunit of the voltage-dependent L-type calcium channel which is important for the development of the action potential in human cardiomyocytes. Pathogenic variants in CACNA1C are the cause for Timothy Syndrome, a rare multi-organ disorder whose manifestations include QT prolongation and ventricular arrhythmias (PMID 15454078). Boczek at al. were the first to identify a variant in CACNA1C in a family with genotype-negative cardiac-specific typical LQTS (PMID 23677916). They performed exome sequencing of 3 members of the family and filtered the shared genetic variants identified using bioinformatics tools. Several other studies have provided additional genetic and experimental evidence to support the association of CACNA1C with typical LQTS, however, no segregation or case-control data is available and the overall level of evidence for this association was classified by the Working Group as moderate. Note: All LQTS genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the LQTS Clinical Domain Working Group. The classification and summary presented here is the conclusion of this Working Group's analysis according to evidence available at time of publication. The scores presented here are the result of only one of the three curation teams' efforts. For a detailed discussion of this group's work and the scores of all 3 teams please see "Adler et al. An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation 2020;141(6):418-428. doi: 10.1161/CIRCULATIONAHA.119.043132”
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