SLC1A2
protein-codingsolute carrier family 1 member 2, the group of Solute carrier family 1
Gene summary
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]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~168.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014916
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014916
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0018614
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014916
Submitter: ClinGen
SLC1A2, encoding excitatory amino acid transporter 2 (EAAT2, GLT-1), was first reported in relation to autosomal dominant early infantile epileptic encephalopathy in 2016 (Epi4K Consortium., PMID: 27476654). Only four de novo missense variants, two of which result in an identical Gly82Arg protein change, have been reported in humans. A single mild recessive case with a homozygous splicing variant has been reported in the literature, however given no other cases and a lack of functional studies they have not been evaluated in this curation. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in six probands in four separate publications (PMIDs: 23934111, 27476654, 28777935, 30937933). Each of these cases stem from a de novo missense variant that affects one of the transmembrane helices in the trimerization domain. The mechanism for disease is a heterozygous dominant negative effect, with missense variants disrupting the monomeric and trimeric structures of the protein causing a reduction of glutamate transport activity by both WT and mutant protein (Stergachis et al., PMID: 30937933). This gene-disease association, in addition to the integral biochemical function of being a CNS glutamate transporter, is also supported by multiple mouse models. A knock-out mouse model showed significantly increased fatality rates due to epileptic seizure activity and susceptibility to brain injury, recapitulating the phenotypes of the human disorder but without the dominant negative mechanism. Similarly, a conditional knock-out of GLT-1 in mouse astrocytes and neurons demonstrates that astrocytic GLT-1 protects against seizures and epilepsy while neuronal GLT-1 is integral to glutamate uptake. This clearly shows that alteration of protein expression can have significant impacts on overall function. In summary, SLC1A2 is definitively associated with autosomal dominant early infantile epileptic encephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time
Inheritance Pattern: AD
Disease ID:MONDO:0014916
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014916
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014916
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SLC1A2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004171.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 124 | 12 | 137 | ||
| missense | 2 | 8 | 202 | 57 | 27 | 296 |
| nonsense | 4 | 4 | ||||
| start loss | 2 | 2 | ||||
| frameshift | 1 | 6 | 7 | |||
| splice donor/acceptor (+/-2bp) | 5 | 1 | 6 | |||
| Total | 2 | 9 | 218 | 184 | 39 | 452 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004162.2 | 11 | MANE Select | |
| Ensembl | ENSP00000278379.3 | 11 | MANE Select | |
| RefSeq | NP_001182657.1 | 10 | Standard | |
| RefSeq | NP_001239581.1 | 10 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| slc1a2b | Danio rerio | Structure: ON-bipolar cell Quality: functionality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Glutamatergic synapse - Homo sapiens (human)
- Amyotrophic lateral sclerosis (ALS) - Homo sapiens (human)
- Astrocytic Glutamate-Glutamine Uptake And Metabolism
- Purine metabolism
- Amino acid and oligopeptide SLC transporters
Biological Process
- ion transport
- chemical synaptic transmission
- visual behavior
- response to wounding
- multicellular organism aging
Molecular Function
- L-glutamate transmembrane transporter activity
- high-affinity glutamate transmembrane transporter activity
- protein binding
- amino acid transmembrane transporter activity
- glutamate:sodium symporter activity
Cellular Component
- plasma membrane
- integral component of plasma membrane
- cell surface
- membrane
- axolemma
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000278379
- Coding exons
- 11
- Length
- 168858
- Individuals with no LoFs
- 125739
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 6
- Defined
- 125745
- p
- 0.0000239
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.28 | 217 | 335 | 0.649 | 0.0000179 | 3756 |
| Missense (PolyPhen) | 55 | 144.97 | 0.37939 | 1632 | ||
| Synonymous | -0.286 | 135 | 131 | 1.03 | 0.00000771 | 1181 |
| Loss of Function | 3.51 | 4 | 21.6 | 0.185 | 0.00000113 | 259 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000035 | 0.000035 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate (PubMed:7521911, PubMed:14506254, PubMed:15265858, PubMed:26690923). Functions as a symporter that transports one amino acid molecule together with two or three Na(+) ions and one proton, in parallel with the counter-transport of one K(+) ion (PubMed:14506254). Mediates Cl(-) flux that is not coupled to amino acid transport; this avoids the accumulation of negative charges due to aspartate and Na(+) symport (PubMed:14506254). Essential for the rapid removal of released glutamate from the synaptic cleft, and for terminating the postsynaptic action of glutamate (By similarity). {ECO:0000250|UniProtKB:P43006, ECO:0000269|PubMed:15265858, ECO:0000269|PubMed:26690923, ECO:0000269|PubMed:7521911}.;
- Disease
- DISEASE: Epileptic encephalopathy, early infantile, 41 (EIEE41) [MIM:617105]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE41 inheritance is autosomal dominant. {ECO:0000269|PubMed:27476654, ECO:0000269|PubMed:28777935}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.385
Intolerance Scores
- LoFtool
- 0.145
- RVIS EVS
- -1.29
- RVIS percentile EVS
- 5.03
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.720
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |