Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
CACNA1C encodes the α1‐subunit of the cardiac L-type calcium channel (CaV1.2) and is implicated in Brugada syndrome (BrS), an autosomal dominant arrhythmia characterized by right precordial ST-segment elevation and risk of sudden cardiac death (MONDO:0015263). Variants in CACNA1C disrupt Ca²⁺ influx and repolarization, predisposing to BrS phenotypes and overlapping short QT intervals (HP:0012232) and arrhythmias (HP:0011675).
Initial evidence arose from a single family in which a missense CACNA1C variant c.898A>G (p.Asn300Asp) was found in four of five BrS patients, segregating with shortened QT and BrS features (PMID:25341504). A splicing variant c.1896G>A (p.Arg632=) causes nonsense-mediated mRNA decay and reduced CACNA1C expression in a BrS patient and his offspring (PMID:24321233). A congenital deaf-mute patient was also reported with a novel CACNA1C mutation in BrS (PMID:28401855).
In larger cohorts, CACNA1C variants were identified in 23 of 205 J-wave syndrome probands (12.3%) and in 9 of 563 BrS probands (1.6%) with functional LoF effects confirmed for nine variants (PMID:20817017; PMID:34999275). The genetic basis review estimates CACNA1C accounts for 5–7% of BrS cases among seven genes screened (PMID:19606473).
Variant spectrum includes missense (e.g., c.3343G>A (p.Glu1115Lys)), synonymous splice (c.1896G>A (p.Arg632=)), and rare deep-intronic changes, all functionally validated. No recurrent or founder alleles have been reported in isolation, suggesting private mutations in diverse populations.
Patch-clamp assays of mutant CaV1.2 channels reveal marked loss-of-function with reduced peak current density, slowed inactivation, and increased window current for p.Asn300Asp and p.Glu1115Lys, recapitulating BrS and short QT phenotypes in human iPSC-derived cardiomyocytes (PMID:25341504; PMID:36007726). Western blot and FRAP studies confirm defective channel expression and membrane dynamics, and computational models reproduce ST-elevation and arrhythmogenesis.
Mechanistically, CACNA1C mutations cause haploinsufficiency via NMD or channel gating defects that reduce inward Ca²⁺ current, shorten action potential plateau, and unmask late Na⁺ currents, promoting arrhythmia. Rescue by CRISPR correction of E1115K restores normal Ca²⁺ selectivity and action potential parameters in iPSC-CMs, underscoring mechanistic concordance.
Some BrS-associated CACNA1C variants are found in general populations without ECG changes or clinical events (n = 28; no type I BrS ECG) indicating incomplete penetrance and variant-specific pathogenicity (PMID:27711072). Rigorous functional validation remains essential for clinical interpretation.
Key Take-home: CACNA1C is a strong BrS susceptibility gene with autosomal dominant inheritance; functional assays are critical to establish pathogenicity of novel variants and guide pre-symptomatic genetic screening and risk stratification.
Gene–Disease AssociationStrongApproximately 20 unrelated probands with CACNA1C variants causing Brugada syndrome, including multiple variant classes and one multi-generational family demonstrating segregation (PMID:25341504) and concordant functional data Genetic EvidenceStrongIdentification of at least 20 probands with 15 distinct functionally validated CACNA1C variants across multiple cohorts (PMID:25341504; PMID:34999275; PMID:36007726) Functional EvidenceModeratePatch-clamp and iPSC-derived cardiomyocyte assays demonstrate CACNA1C mutations cause CaV1.2 loss-of-function or gating defects consistent with BrS phenotypes (PMID:25341504; PMID:36007726) |