GABRB1

Chr 4AD

gamma-aminobutyric acid type A receptor subunit beta1

Also known as: DEE45, EIEE45

NCBI Gene: 2560 ENSG00000163288 UniProt: P18505 OMIM: 137190

The beta 1 subunit of the GABA-A receptor forms part of a multisubunit chloride channel that mediates fast inhibitory synaptic transmission in the central nervous system. Autosomal dominant mutations cause developmental and epileptic encephalopathy 45 through a gain-of-function mechanism. The gene is highly intolerant to loss-of-function variants, indicating that haploinsufficiency is not the pathogenic mechanism for this condition.

OMIM ResearchSummary from RefSeq, OMIM, 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 GABA A receptor, beta 1 subunit. It is mapped to chromosome 4p12 in a cluster comprised of genes encoding alpha 4, alpha 2 and gamma 1 subunits of the GABA A receptor. Alteration of this gene is implicated in the pathogenetics of schizophrenia. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.311 OMIM phenotype

Clinical Summary— GABRB1

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Gene-Disease Validity (ClinGen)

genetic developmental and epileptic encephalopathy · ADLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 218 VUS of 448 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.31LOEUF

pLI 0.981

Z-score 4.11

OE 0.12 (0.05–0.31)

Highly constrained

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

Missense Constraint?

2.65Z-score

OE missense 0.55 (0.49–0.63)

156 obs / 281.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.12 (0.05–0.31)

0≤0.351.4

Missense OE?0.55 (0.49–0.63)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 3 / 25.3Missense obs/exp: 156 / 281.1Syn Z: -1.00

This gene — mechanism propensity

0.6840th %ile

GOF

0.74top 25%

LOF

0.4726th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.31

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

448 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic4

VUS218

Likely Benign194

Benign24

Conflicting5

Pathogenic

Likely Pathogenic

218

VUS

194

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	0	4	0	0	4
VUS	13	191	13	1	218
Likely Benign	0	2	83	109	194
Benign	0	1	12	11	24
Conflicting	—				5
Total	13	199	108	121	446

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 GABRB1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →