GABBR1

Chr 6AD

gamma-aminobutyric acid type B receptor subunit 1

Also known as: GABABR1, GABBR1-3, GB1, GPRC3A, NEDLC

NCBI Gene: 2550 ENSG00000204681 UniProt: Q9UBS5 OMIM: 603540

The GABBR1 protein forms a heterodimeric G-protein coupled receptor with GABBR2 that binds GABA and fine-tunes inhibitory synaptic transmission by modulating calcium channels and potassium conductance. Mutations cause autosomal dominant neurodevelopmental disorder with language delay and variable cognitive abnormalities. This gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.22), indicating that functional copies are critical for normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a receptor for gamma-aminobutyric acid (GABA), which is the main inhibitory neurotransmitter in the mammalian central nervous system. This receptor functions as a heterodimer with GABA(B) receptor 2. Defects in this gene may underlie brain disorders such as schizophrenia and epilepsy. Alternative splicing generates multiple transcript variants, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jan 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.221 OMIM phenotype

Clinical Summary— GABBR1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

8 unique Pathogenic / Likely Pathogenic· 140 VUS of 190 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.22LOEUF

pLI 1.000

Z-score 5.98

OE 0.11 (0.06–0.22)

Highly constrained

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

Missense Constraint?

4.82Z-score

OE missense 0.42 (0.38–0.47)

236 obs / 555.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.11 (0.06–0.22)

0≤0.351.4

Missense OE?0.42 (0.38–0.47)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 6 / 53.0Missense obs/exp: 236 / 555.8Syn Z: 0.89

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateGABBR1-related neurodevelopmental disorderOTHERAD

This gene — mechanism propensity

0.4983th %ile

GOF

0.6540th %ile

LOF

0.59top 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.

LOFLOEUF 0.22

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

ClinVar Variant Classifications

190 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic8

VUS140

Likely Benign13

Benign3

Conflicting1

Likely Pathogenic

140

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	8	0	0	8
VUS	16	118	4	2	140
Likely Benign	0	3	1	9	13
Benign	0	0	0	3	3
Conflicting	—				1
Total	16	129	5	14	165

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 9) ClinVar copy-number / structural variants overlap GABBR1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →