SLC1A2

Chr 11AD

solute carrier family 1 member 2

Also known as: DEE41, EAAT2, EIEE41, GLT-1, GLT1, HBGT

NCBI Gene: 6506 ENSG00000110436 UniProt: P43004 OMIM: 600300

This gene encodes the principal transporter that clears glutamate from synapses in the central nervous system, preventing neuronal damage from excessive glutamate receptor activation. Mutations cause developmental and epileptic encephalopathy 41 through an autosomal dominant inheritance pattern. The pathogenic mechanism involves gain-of-function mutations that disrupt normal glutamate clearance regulation.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

GOF/LOFmechanismADLOEUF 0.421 OMIM phenotype

Clinical Summary— SLC1A2

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Gene-Disease Validity (ClinGen)

developmental and epileptic encephalopathy, 41 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.71) — some intolerance to loss-of-function variants.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint

0.42LOEUF

pLI 0.710

Z-score 3.51

OE 0.19 (0.09–0.42)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

2.28Z-score

OE missense 0.65 (0.58–0.73)

217 obs / 334.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.19 (0.09–0.42)

0≤0.351.4

Missense OE0.65 (0.58–0.73)

0≤0.61.4

Synonymous OE1.03

0≤1.21.6

LoF obs/exp: 4 / 21.6Missense obs/exp: 217 / 334.6Syn Z: -0.29

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongSLC1A2-related epileptic encephalopathyOTHERAD

Mechanism Note (variant-dependent)

GOFLOF— mechanism depends on specific variant

Glutamate transporter EAAT2. GOF variants (increased glutamate uptake) and LOF variants (reduced clearance) both cause DEE. Mechanism is variant-specific.

References:PMID:31645364

0.7131th %ile

GOF

0.82top 10%

LOF

0.3455th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction 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

DNRecurrent SLC1A2 variants cause epilepsy via a dominant negative mechanism.PMID:30937933

GOFWith the identification of both known and previously unreported mutations, our study provides further evidence for SLC1A2 mutations in EE and suggests a gain-of-function mechanism for this rather severe presentationPMID:28777935

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.