SLC1A2

Chr 11AD

solute carrier family 1 member 2

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

This gene encodes a member of a family of solute transporter proteins. The membrane-bound protein is the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage from excessive activation of glutamate receptors. Improper regulation of this gene is thought to be associated with several neurological disorders. Alternatively spliced transcript variants of this gene have been identified. [provided by RefSeq, Jun 2017]

GeneReviewsOMIMResearchGenerating clinical summary…
GOF/LOFmechanismADLOEUF 0.421 OMIM phenotype
Clinical SummarySLC1A2
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Gene-Disease Validity (ClinGen)
developmental and epileptic encephalopathy, 41 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.71) — some intolerance to loss-of-function variants.
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ClinVar Variants
10 unique Pathogenic / Likely Pathogenic· 214 VUS of 540 total submissions
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GeneReview available — SLC1A2
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Moderate LoF intolerance
LoF Constraint?
0.42LOEUF
pLI 0.710
Z-score 3.51
OE 0.19 (0.090.42)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?
2.28Z-score
OE missense 0.65 (0.580.73)
217 obs / 334.6 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?
LoF OE?0.19 (0.090.42)
00.351.4
Missense OE?0.65 (0.580.73)
00.61.4
Synonymous OE?1.03
01.21.6
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.1

This gene — mechanism propensity

DN
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 · 90% of P/LP are missense
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.2
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 presentation3

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

540 submitted variants in ClinVar

Classification Summary

Pathogenic2
Likely Pathogenic8
VUS214
Likely Benign230
Benign61
Conflicting17
2
Pathogenic
8
Likely Pathogenic
214
VUS
230
Likely Benign
61
Benign
17
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
0
0
2
Likely Pathogenic
1
7
0
0
8
VUS
13
193
7
1
214
Likely Benign
1
42
74
113
230
Benign
0
28
14
19
61
Conflicting
17
Total1527295133532

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

View in ClinVar →

18 pathogenic / likely-pathogenic (of 28) ClinVar copy-number / structural variants overlap SLC1A2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

SLC1A2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →