GABRQ

Chr X

gamma-aminobutyric acid type A receptor subunit theta

Also known as: THETA

NCBI Gene: 55879 ENSG00000268089 UniProt: Q9UN88 OMIM: 300349

The protein encodes the theta subunit of GABA-A receptors, which are heteropentameric chloride channels that mediate fast inhibitory synaptic transmission in the central nervous system by allowing chloride influx when activated by GABA. Mutations cause X-linked intellectual disability and epilepsy through a gain-of-function mechanism that disrupts normal inhibitory neurotransmission. The gene is located on chromosome Xq28 and follows X-linked inheritance.

OMIM ResearchSummary from RefSeq, UniProt, Mechanism

The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes the theta subunit of the GABA A receptor. The gene is mapped to chromosome Xq28 in a cluster of genes including those that encode the alpha 3 and epsilon subunits of the GABA A receptor. [provided by RefSeq, Jul 2017]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.74

Clinical Summary— GABRQ

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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?

0.74LOEUF

pLI 0.004

Z-score 2.38

OE 0.39 (0.22–0.74)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.58Z-score

OE missense 0.90 (0.81–1.00)

246 obs / 273.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.39 (0.22–0.74)

0≤0.351.4

Missense OE?0.90 (0.81–1.00)

0≤0.61.4

Synonymous OE?0.79

0≤1.21.6

LoF obs/exp: 7 / 17.9Missense obs/exp: 246 / 273.0Syn Z: 1.71

This gene — mechanism propensity

0.81top 10%

GOF

0.86top 5%

LOF

0.1697th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-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

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.

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