GABRE

Chr X

gamma-aminobutyric acid type A receptor subunit epsilon

NCBI Gene: 2564 ENSG00000102287 OMIM: 300093

The epsilon subunit of GABA-A receptors forms part of heteropentameric chloride channels that mediate fast inhibitory neurotransmission in the brain and allow spontaneous chloride channel activity. Mutations cause early infantile epileptic encephalopathy and Ohtahara syndrome with X-linked inheritance. This gene shows low constraint to loss-of-function variants, and phenotypes may include both neurological and cardiac manifestations.

OMIM ResearchSummary from RefSeq, UniProt

The product of this gene belongs to the ligand-gated ionic channel (TC 1.A.9) family. It encodes the gamma-aminobutyric acid (GABA) A receptor which is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes an epsilon subunit. It is mapped to chromosome Xq28 in a cluster comprised of genes encoding alpha 3, beta 4 and theta subunits of the same receptor. Alternatively spliced transcript variants have been identified, but only one is thought to encode a protein. [provided by RefSeq, Oct 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.02

Clinical Summary— GABRE

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.02LOEUF

pLI 0.000

Z-score 1.51

OE 0.57 (0.33–1.02)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.07Z-score

OE missense 1.01 (0.91–1.14)

211 obs / 208.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.57 (0.33–1.02)

0≤0.351.4

Missense OE?1.01 (0.91–1.14)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 8 / 14.1Missense obs/exp: 211 / 208.1Syn Z: 0.61

This gene — mechanism propensity

0.77top 25%

GOF

0.76top 25%

LOF

0.2580th %ile

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

DNprediction above median

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.