CACNA1C – Long QT Syndrome

CACNA1C encodes the α1‐subunit of the cardiac L-type Ca2+ channel CaV1.2. Heterozygous missense mutations in CACNA1C have been reported in patients with congenital long QT syndrome (LQTS), including type 8 (Timothy syndrome) and isolated QT prolongation, with autosomal dominant inheritance. Gain-of-function variants perturb channel gating, leading to prolonged repolarization and ventricular arrhythmias.

ClinGen places the CACNA1C–LQTS association in the Strong category based on evidence from >10 unrelated probands, a multigenerational pedigree with co-segregation, and multiple concordant functional studies. This meets the criteria for robust clinical validity given replication across families and consistent electrophysiological phenotypes.

Inheritance is autosomal dominant. Segregation analysis in a multigenerational pedigree demonstrated co-segregation of the CACNA1C c.2570C>G (p.Pro857Arg) variant with LQTS in three affected relatives ([PMID:23677916]). Case series include seven independent probands carrying novel CACNA1C variants such as c.5347G>T (p.Gly1783Cys) in a cohort of 278 genotype-negative LQTS patients ([PMID:24728418]), plus single-case reports of c.5731G>A (p.Gly1911Arg) ([PMID:25184293]) and c.3343G>A (p.Glu1115Lys) ([PMID:36007726]). The variant spectrum is dominated by missense gain-of-function changes.

Functional assays in heterologous systems and patient-derived iPSC-cardiomyocytes consistently demonstrate that pathogenic CACNA1C mutations reduce voltage-dependent inactivation, shift activation/inactivation kinetics, and increase window current. For example, p.Gly1911Arg slows inactivation and enhances sustained current ([PMID:25184293]), while p.Glu1115Lys impairs Ca2+ selectivity and prolongs action potentials in iPSC-CMs ([PMID:36007726]). These data concordantly recapitulate the human phenotype.

However, whole-exome sequencing studies indicate that rare CACNA1C variants are also detected in healthy populations at similar frequencies to LQTS cases, suggesting background genetic noise ([PMID:29501670]). This underscores the need for functional validation and careful phenotype correlation in variant interpretation.

In conclusion, autosomal dominant gain-of-function CACNA1C variants are strongly associated with LQTS type 8. Genetic testing of CACNA1C should be included in diagnostic panels for unexplained QT prolongation, and functional studies remain essential to distinguish pathogenic mutations from benign variation.

References

• PLoS One • 2014 • A CACNA1C variant associated with reduced voltage-dependent inactivation, increased CaV1.2 channel window current, and arrhythmogenesis. PMID:25184293
• Circulation: Cardiovascular Genetics • 2013 • Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome. PMID:23677916
• Europace • 2014 • Long QT syndrome type 8: novel CACNA1C mutations causing QT prolongation and variant phenotypes. PMID:24728418
• Heart Rhythm • 2023 • Disrupted CaV1.2 selectivity causes overlapping long QT and Brugada syndrome phenotypes in the CACNA1C-E1115K iPS cell model. PMID:36007726
• Heart Rhythm • 2018 • Amino acid-level signal-to-noise analysis of incidentally identified variants in genes associated with long QT syndrome during pediatric whole exome sequencing reflects background genetic noise. PMID:29501670

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