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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

10 unique Pathogenic / Likely Pathogenic· 214 VUS of 540 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SLC1A2

Authoritative clinical overview · Recommended first read

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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 OE?0.19 (0.09–0.42)

0≤0.351.4

Missense OE?0.65 (0.58–0.73)

0≤0.61.4

Synonymous OE?1.03

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.1

This gene — mechanism propensity

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.

References

ClinVar Variant Classifications

540 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic8

VUS214

Likely Benign230

Benign61

Conflicting17

Pathogenic

Likely Pathogenic

214

VUS

230

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	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
Total	15	272	95	133	532

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 →