GABRA1

Chr 5AD

gamma-aminobutyric acid type A receptor subunit alpha1

Also known as: DEE19, ECA4, EIEE19, EJM, EJM5

NCBI Gene: 2554 ENSG00000022355 UniProt: P14867 OMIM: 137160

The protein functions as the alpha-1 subunit of GABA-A receptors, heteropentameric ligand-gated chloride channels that mediate inhibitory neurotransmission in the brain. Mutations cause developmental and epileptic encephalopathy 19, childhood absence epilepsy, and juvenile myoclonic epilepsy through an autosomal dominant inheritance pattern. Disease mechanisms are variant-dependent, with mutations causing pathogenicity through either loss-of-function or dominant-negative effects.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

GOF/LOFmechanismADLOEUF 0.373 OMIM phenotypes

Clinical Summary— GABRA1

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Gene-Disease Validity (ClinGen)

epilepsy · 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 0.91). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — 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

0.37LOEUF

pLI 0.915

Z-score 3.65

OE 0.14 (0.06–0.37)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

3.15Z-score

OE missense 0.43 (0.37–0.51)

105 obs / 243.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.14 (0.06–0.37)

0≤0.351.4

Missense OE0.43 (0.37–0.51)

0≤0.61.4

Synonymous OE1.25

0≤1.21.6

LoF obs/exp: 3 / 21.1Missense obs/exp: 105 / 243.2Syn Z: -1.91

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongGABRA1-related epileptic encephalopathyOTHERAD

strongGABRA1-related juvenile myoclonic epilepsyLOFAD

Mechanism Note (variant-dependent)

LOFDN— mechanism depends on specific variant

GABA-A receptor alpha-1 subunit. Truncating variants cause haploinsufficiency (LOF) leading to DEE. Some missense variants cause dominant-negative effects on pentameric assembly. GOF is not an established mechanism.

References:PMID:16945118

0.6259th %ile

GOF

0.72top 25%

LOF

0.50top 25%

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, 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 dominant-negative. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

LOF1 literature citation · LOEUF 0.37

GOFprediction above median

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

DNThese findings demonstrated that, in addition to causing a heterozygous loss of function of alpha1(AD) subunits, this epilepsy mutation also elicited a modest dominant negative effect that likely shapes the epilepsy phenotype.PMID:20551311

LOFWe conclude that this de novo mutation can contribute to the cause of """"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""sporadic"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""" childhood absence epilepsy by a loss of function and haploinsufficiency of the GABA(A) receptPMID:16718694

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