GABRG1

Chr 4

gamma-aminobutyric acid type A receptor subunit gamma1

NCBI Gene: 2565 ENSG00000163285 UniProt: Q8N1C3 OMIM: 137166

The gamma-1 subunit forms part of GABA(A) receptors, heteropentameric chloride channels that mediate inhibitory neurotransmission in the brain by allowing chloride influx when activated by GABA. Mutations cause autosomal recessive early infantile epileptic encephalopathy-89, characterized by severe seizures beginning in early infancy. This gene is not highly constrained against loss-of-function variants, which is consistent with the recessive inheritance pattern observed in affected patients.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene belongs to the ligand-gated ionic channel family. It is an integral membrane protein and plays an important role in inhibiting neurotransmission by binding to the benzodiazepine receptor and opening an integral chloride channel. This gene is clustered with three other family members on chromosome 4. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.81

Clinical Summary— GABRG1

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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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ClinVar Variants

58 VUS of 63 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.81LOEUF

pLI 0.000

Z-score 2.22

OE 0.48 (0.29–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.52Z-score

OE missense 0.91 (0.81–1.01)

220 obs / 242.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.48 (0.29–0.81)

0≤0.351.4

Missense OE?0.91 (0.81–1.01)

0≤0.61.4

Synonymous OE?1.20

0≤1.21.6

LoF obs/exp: 10 / 21.0Missense obs/exp: 220 / 242.8Syn Z: -1.46

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedGABRG1-related epileptic encephalopathyOTHERAD

This gene — mechanism propensity

0.85top 5%

GOF

0.82top 10%

LOF

0.2092th %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.

ClinVar Variant Classifications

63 submitted variants in ClinVar

ClinVar

Classification Summary

VUS58

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	58	0	58
Likely Benign	0	1	1
Benign	0	0	0
Total	58	1	59

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 24) ClinVar copy-number / structural variants overlap GABRG1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →