GABRA5

Chr 15AD

gamma-aminobutyric acid type A receptor subunit alpha5

Also known as: DEE79, EIEE79

NCBI Gene: 2558 ENSG00000186297 UniProt: P31644 OMIM: 137142

The protein encoded by this gene forms part of GABA-A receptors, which are ligand-gated chloride channels that mediate the major inhibitory neurotransmission in the brain. Mutations cause developmental and epileptic encephalopathy 79 through an autosomal dominant inheritance pattern via a gain-of-function mechanism. The gene is highly constrained against loss-of-function variants, consistent with the pathogenic mechanism being gain-of-function rather than haploinsufficiency.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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. At least 16 distinct subunits of GABA-A receptors have been identified. Transcript variants utilizing three different alternative non-coding first exons have been described. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.371 OMIM phenotype

Clinical Summary— GABRA5

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.91). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 74 VUS of 132 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?

0.37LOEUF

pLI 0.905

Z-score 3.62

OE 0.14 (0.07–0.37)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.23Z-score

OE missense 0.46 (0.39–0.53)

127 obs / 278.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.14 (0.07–0.37)

0≤0.351.4

Missense OE?0.46 (0.39–0.53)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 3 / 20.8Missense obs/exp: 127 / 278.8Syn Z: -0.25

This gene — mechanism propensity

0.6937th %ile

GOF

0.75top 25%

LOF

0.4430th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-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 dominant-negative. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median

LOFLOEUF 0.37

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

DNFurthermore, mutant a5(S413F)HA subunits had a dominant negative effect by decreasing the trafficking of partnering b3 (0.65 ± 0.06, P = 0.0003, n = 4) and g2 (0.65 ± 0.06, P = 0.0106, n = 4) subunits to the surface (Fig. 3C, middle and bottom). Mutant a5(S413F)HA subunits had a dominant negative ef1

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 31056671 ↗

ClinVar Variant Classifications

132 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic3

VUS74

Likely Benign37

Benign12

Conflicting1

Pathogenic

Likely Pathogenic

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	2	1	0	3
Likely Pathogenic	0	3	0	0	3
VUS	5	65	3	1	74
Likely Benign	0	6	5	26	37
Benign	0	1	5	6	12
Conflicting	—				1
Total	5	77	14	33	130

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

View in ClinVar →

305 pathogenic / likely-pathogenic (of 312) ClinVar copy-number / structural variants overlap GABRA5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →