CACNA1E

Chr 1

calcium voltage-gated channel subunit alpha1 E

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

NCBI Gene: 777 ENSG00000198216 UniProt: Q15878

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.

ResearchSummary from RefSeq, OMIM, UniProt

Voltage-dependent calcium channels are multisubunit complexes consisting of alpha-1, alpha-2, beta, and delta subunits in a 1:1:1:1 ratio. These channels mediate the entry of calcium ions into excitable cells, and 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. This gene encodes the alpha-1E subunit of the R-type calcium channels, which belong to the 'high-voltage activated' group that maybe involved in the modulation of firing patterns of neurons important for information processing. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Apr 2011]

ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.12

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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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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