GABRD

Chr 1AD

gamma-aminobutyric acid type A receptor subunit delta

Also known as: EIG10, EJM7, GABAARdelta, GEFSP5

NCBI Gene: 2563 ENSG00000187730 UniProt: O14764 OMIM: 137163

The protein encodes the delta subunit of GABA-A receptors, which are pentameric ligand-gated chloride channels that mediate inhibitory neurotransmission in the brain. Mutations cause autosomal dominant generalized epilepsy with febrile seizures plus, type 5 through a predicted gain-of-function mechanism. The gene is highly intolerant to loss-of-function variants, consistent with the gain-of-function pathogenic mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. The GABA-A receptor is generally pentameric and there are five types of subunits: alpha, beta, gamma, delta, and rho. This gene encodes the delta subunit. Mutations in this gene have been associated with susceptibility to generalized epilepsy with febrile seizures, type 5. Alternatively spliced transcript variants have been described for this gene, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.241 OMIM phenotype

Clinical Summary— GABRD

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.24LOEUF

pLI 0.993

Z-score 3.87

OE 0.05 (0.02–0.24)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.17Z-score

OE missense 0.64 (0.57–0.73)

189 obs / 293.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.24)

0≤0.351.4

Missense OE?0.64 (0.57–0.73)

0≤0.61.4

Synonymous OE?1.24

0≤1.21.6

LoF obs/exp: 1 / 19.4Missense obs/exp: 189 / 293.5Syn Z: -2.23

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateGABRD-related neurodevelopmental disorder with epilepsyGOFAD

This gene — mechanism propensity

0.6452th %ile

GOF

0.73top 25%

LOF

0.4726th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, loss-of-function and dominant-negative). 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 0.24

DNprediction 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

GOFGain-of-function variants in GABRD reveal a novel pathway for neurodevelopmental disorders and epilepsy.1

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

References