CACNA1C

Chr 12AD

calcium voltage-gated channel subunit alpha1 C

Also known as: CACH2, CACN2, CACNA1C-IT2, CACNL1A1, CCHL1A1, CaV1.2, LQT8, NEDHLSS

NCBI Gene: 775 ENSG00000151067 UniProt: Q13936 OMIM: 114205

The protein forms the pore-forming alpha-1C subunit of voltage-gated L-type calcium channels, mediating calcium influx that is essential for cardiac excitation-contraction coupling, smooth muscle contraction, and blood pressure regulation. Mutations cause autosomal dominant Timothy syndrome, Brugada syndrome 3, long QT syndrome 8, and neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures. The gene is extremely intolerant to loss-of-function variants, and mutations can cause disease through multiple mechanisms depending on the specific variant type.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

GOFmechanismADLOEUF 0.104 OMIM phenotypes

Clinical Summary— CACNA1C

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Gene-Disease Validity (ClinGen)

short QT syndrome · ADDisputed

Disputed — evidence questions this relationship

4 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.10LOEUF

pLI 1.000

Z-score 8.94

OE 0.05 (0.02–0.10)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint

6.47Z-score

OE missense 0.50 (0.46–0.53)

643 obs / 1298.7 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios

LoF OE0.05 (0.02–0.10)

0≤0.351.4

Missense OE0.50 (0.46–0.53)

0≤0.61.4

Synonymous OE0.99

0≤1.21.6

LoF obs/exp: 5 / 102.7Missense obs/exp: 643 / 1298.7Syn Z: 0.11

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedCACNA1C-related short QT syndromeOTHERAD

limitedCACNA1C-related Brugada syndromeOTHERAD

definitiveCACNA1C-related Timothy syndromeGOFAD

0.5576th %ile

GOF

0.73top 25%

LOF

0.59top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · LOEUF 0.10

GOFprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFThe identification of a functional CACNA1C mutation cosegregating with disease in a single pedigree suggests that CACNA1C perturbations may underlie autosomal dominant LQTS in the absence of Timothy syndrome.PMID:23677916

LOFPhenotype-genotype comparison between our case, previously reported patients, and subjects with 12p13.33 deletions led us to propose that haploinsufficiency of CACNA1C may influence the variability of the patients' phenotype, since the gene resulted disrupted or entirely deleted in the majority of rPMID:24780630

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.