SLC6A1

Chr 3AD

solute carrier family 6 member 1

Also known as: GABATHG, GABATR, GAT1, MAE, hGAT-1

NCBI Gene: 6529 ENSG00000157103 UniProt: P30531 OMIM: 137165

The protein functions as a gamma-aminobutyric acid (GABA) transporter that removes GABA from the synaptic cleft and restores it to presynaptic terminals. Mutations cause myoclonic-atonic epilepsy through autosomal dominant inheritance. The gene is highly intolerant to loss-of-function variants, suggesting mutations predominantly cause disease through haploinsufficiency affecting GABAergic neurotransmission.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a gamma-aminobutyric acid (GABA) transporter that localizes to the plasma membrane. The encoded protein removes GABA from the synaptic cleft, restoring it to presynaptic terminals. [provided by RefSeq, Jan 2017]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.151 OMIM phenotype

Clinical Summary— SLC6A1

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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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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

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?

0.15LOEUF

pLI 1.000

Z-score 5.05

OE 0.03 (0.01–0.15)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

4.18Z-score

OE missense 0.39 (0.34–0.45)

144 obs / 370.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.03 (0.01–0.15)

0≤0.351.4

Missense OE?0.39 (0.34–0.45)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 1 / 31.7Missense obs/exp: 144 / 370.1Syn Z: -0.96

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSLC6A1-related epilepsy with myoclonic-atonic seizuresLOFAD

This gene — mechanism propensity

0.5672th %ile

GOF

0.72top 25%

LOF

0.50top 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.

LOF1 literature citation · LOEUF 0.15 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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.

Literature Evidence

LOFRange of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References