GABRB3

Chr 15AD

gamma-aminobutyric acid type A receptor subunit beta3

Also known as: DEE43, ECA5, EIEE43

NCBI Gene: 2562 ENSG00000166206 UniProt: P28472 OMIM: 137192

The protein is the beta-3 subunit of GABA(A) receptors, heteropentameric ligand-gated chloride channels that mediate GABAergic inhibition in the brain by allowing chloride influx and reducing neuronal excitability. Mutations cause developmental and epileptic encephalopathy 43 and childhood absence epilepsy through an autosomal dominant inheritance pattern. The gene is highly intolerant to loss-of-function variants, and mutations can cause disease through multiple mechanisms depending on the specific variant.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the ligand-gated ionic channel family. The encoded protein is one the subunits of a multi-subunit chloride channel that serves as the receptor for gamma-aminobutyric acid, a major inhibitory neurotransmitter of the mammalian nervous system. This gene is located on the long arm of chromosome 15 in a cluster with two other genes encoding related subunits of the family. This gene may be associated with the pathogenesis of several disorders including Angelman syndrome, Prader-Willi syndrome, nonsyndromic orofacial clefts, epilepsy and autism. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2013]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.342 OMIM phenotypes

Clinical Summary— GABRB3

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Gene-Disease Validity (ClinGen)

genetic developmental and epileptic encephalopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.95). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

109 unique Pathogenic / Likely Pathogenic· 312 VUS of 790 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GABRB3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.34LOEUF

pLI 0.951

Z-score 3.83

OE 0.13 (0.06–0.34)

Highly constrained

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

Missense Constraint?

3.39Z-score

OE missense 0.41 (0.35–0.48)

107 obs / 260.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.13 (0.06–0.34)

0≤0.351.4

Missense OE?0.41 (0.35–0.48)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 3 / 22.7Missense obs/exp: 107 / 260.9Syn Z: -0.72

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGABRB3-related childhood absence epilepsyOTHERAD

This gene — mechanism propensity

0.5966th %ile

GOF

0.6832th %ile

LOF

0.56top 25%

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

LOF23% of P/LP variants are LoF · LOEUF 0.34

GOFprediction above median · 1 literature citation

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 GABRB3 variants identified in vigabatrin-hypersensitive epileptic encephalopathies.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

1.PMID 33585817 ↗

ClinVar Variant Classifications

790 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic47

Likely Pathogenic62

VUS312

Likely Benign276

Benign52

Conflicting32

Pathogenic

Likely Pathogenic

312

VUS

276

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	18	20	9	0	47
Likely Pathogenic	7	55	0	0	62
VUS	21	259	31	1	312
Likely Benign	0	19	124	133	276
Benign	1	6	41	4	52
Conflicting	—				32
Total	47	359	205	138	781

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

View in ClinVar →

305 pathogenic / likely-pathogenic (of 316) ClinVar copy-number / structural variants overlap GABRB3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →