CACNA1E

Chr 1AD

calcium voltage-gated channel subunit alpha1 E

ENSG00000198216 UniProt: Q15878 OMIM: 601013

The protein forms the alpha-1E subunit of R-type voltage-dependent calcium channels that mediate calcium entry into excitable cells and modulate neuronal firing patterns important for information processing. Mutations cause developmental and epileptic encephalopathy 69 with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants, and mutations can cause disease through multiple mechanisms depending on the specific variant type.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells (PubMed:30343943). They are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1E gives rise to R-type calcium currents. R-type calcium channels belong to the 'high-voltage activated' (HVA) group and are blocked by nickel. They are however insensitive to dihydropyridines (DHP). Calcium channels containing alpha-1E subunit could be involved in the modulation of firing patterns of neurons which is important for information processing

OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.121 OMIM phenotype

Clinical Summary— CACNA1E

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Gene-Disease Validity (ClinGen)

genetic developmental and epileptic encephalopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.12LOEUF

pLI 1.000

Z-score 9.29

OE 0.07 (0.04–0.12)

Highly constrained

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

Missense Constraint?

5.81Z-score

OE missense 0.56 (0.52–0.59)

750 obs / 1351.3 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.07 (0.04–0.12)

0≤0.351.4

Missense OE?0.56 (0.52–0.59)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 8 / 115.9Missense obs/exp: 750 / 1351.3Syn Z: -0.21

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCACNA1E-related epileptic encephalopathy with contractures, macrocephaly, and dyskinesiaGOFAD

Mechanism Note (expert annotation)

GOF

Cav2.3 alpha subunit is monomeric at the pore level. DEE69 variants cause GOF with increased calcium influx and shifted voltage dependence.1

This gene — mechanism propensity

0.5378th %ile

GOF

0.6833th %ile

LOF

0.61top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

LOFLOEUF 0.12

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

GOFThere were several recurrent mutations. In vitro functional expression studies of some of the mutations in human tsA201 transformed kidney cells showed that they resulted in consistent gain-of-function effects, including facilitated voltage-dependent channel activation, slowed inactivation, and incr2

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

References