CACNA1E

Chr 1AD

calcium voltage-gated channel subunit alpha1 E

Also known as: BII, CACH6, CACNL1A6, Cav2.3, DEE69, EIEE69, gm139

NCBI Gene: 777 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

GOFmechanismADLOEUF 0.121 OMIM phenotype

Clinical Summary— CACNA1E

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Gene-Disease Validity (ClinGen)

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 OE0.07 (0.04–0.12)

0≤0.351.4

Missense OE0.56 (0.52–0.59)

0≤0.61.4

Synonymous OE1.01

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.

References:PMID:30531870

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 incrPMID:30343943

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