GABRG3

Chr 15

gamma-aminobutyric acid type A receptor subunit gamma3

NCBI Gene: 2567 ENSG00000182256 UniProt: Q99928 OMIM: 600233

The GABRG3 protein is a gamma subunit of GABA-A receptors, pentameric ligand-gated chloride channels that mediate inhibitory neurotransmission in the brain and contain the benzodiazepine binding site. Mutations cause autosomal recessive epileptic encephalopathy with intellectual disability and developmental delays. This gene is highly constrained against loss-of-function variants (pLI 0.85, LOEUF 0.39), indicating that such mutations are likely to have significant clinical consequences.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a gamma-aminobutyric acid (GABA) receptor. 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. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. The protein encoded by this gene is a gamma subunit, which contains the benzodiazepine binding site. Two transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Aug 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.39

Clinical Summary— GABRG3

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.85) — some intolerance to loss-of-function variants.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 39 VUS of 57 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.39LOEUF

pLI 0.847

Z-score 3.76

OE 0.17 (0.08–0.39)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.52Z-score

OE missense 0.56 (0.49–0.64)

145 obs / 259.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.17 (0.08–0.39)

0≤0.351.4

Missense OE?0.56 (0.49–0.64)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 4 / 23.8Missense obs/exp: 145 / 259.1Syn Z: -0.17

This gene — mechanism propensity

0.6840th %ile

GOF

0.72top 25%

LOF

0.4135th %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.

ClinVar Variant Classifications

57 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS39

Likely Benign4

Benign4

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	1	1
Likely Pathogenic	0	0	0	0	0
VUS	1	37	0	1	39
Likely Benign	0	4	0	0	4
Benign	0	0	1	3	4
Total	1	41	1	5	48

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

305 pathogenic / likely-pathogenic (of 317) ClinVar copy-number / structural variants overlap GABRG3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →