CACNA1E

Chr 1AD

calcium voltage-gated channel subunit alpha1 E

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

OMIMResearchGenerating clinical summary…
GOFmechanismADLOEUF 0.121 OMIM phenotype
Clinical SummaryCACNA1E
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Gene-Disease Validity (ClinGen)
genetic developmental and epileptic encephalopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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.
Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Dual constrained — LoF & missense intolerant
LoF Constraint?
0.12LOEUF
pLI 1.000
Z-score 9.29
OE 0.07 (0.040.12)
Highly constrained

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

Missense Constraint?
5.81Z-score
OE missense 0.56 (0.520.59)
750 obs / 1351.3 exp
Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?
LoF OE?0.07 (0.040.12)
00.351.4
Missense OE?0.56 (0.520.59)
00.61.4
Synonymous OE?1.01
01.21.6
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

DN
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.

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

CACNA1E · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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