GeneBe

SLC2A1

protein-coding

solute carrier family 2 member 1, the group of Solute carrier family 2

Gene summary

This gene encodes a major glucose transporter in the mammalian blood-brain barrier. The encoded protein is found primarily in the cell membrane and on the cell surface, where it can also function as a receptor for human T-cell leukemia virus (HTLV) I and II. Mutations in this gene have been found in a family with paroxysmal exertion-induced dyskinesia. [provided by RefSeq, Apr 2013]

Previous symbols:
  • GLUT1
  • GLUT
  • HTLVR
  • CSE

MANE transcript

NM_006516.4

Inheritance

AD, SD, AR

ClinVar variants

P:354U:380B:222

Top phenotype

GLUT1 deficiency syndrome 1; GLUT1 deficiency syndrome 2; Dystonia 9; Epilepsy, idiopathic generalized, susceptibility to, 12; Stomatin-deficient cryohydrocytosis with neurologic defects

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr1:42,925,353-42,958,893

External References & Databases

Ensembl (ENSG00000117394)NCBI Gene (6513)OMIM (138140)HGNC:11005GenCCUniProt (P11166)AlphaFoldClinVar (SLC2A1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~33.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

dystonia 9STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010983

Submitter: Labcorp Genetics (formerly Invitae)

dystonia 9STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010983

Submitter: Genomics England PanelApp

childhood onset GLUT1 deficiency syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012805

Submitter: Genomics England PanelApp

encephalopathy due to GLUT1 deficiencySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011724

Submitter: Labcorp Genetics (formerly Invitae)

GLUT1 deficiency syndromeSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0000188

Submitter: PanelApp Australia

epilepsy, idiopathic generalized, susceptibility to, 12STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013919

Submitter: Labcorp Genetics (formerly Invitae)

childhood onset GLUT1 deficiency syndrome 2SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012805

Submitter: Orphanet

hereditary cryohydrocytosis with reduced stomatinSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012143

Submitter: Orphanet

dystonia 9SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010983

Submitter: Orphanet

myoclonic-astatic epilepsySUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0016025

Submitter: Orphanet

childhood absence epilepsySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010826

Submitter: Orphanet

encephalopathy due to GLUT1 deficiencySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011724

Submitter: Orphanet

encephalopathy due to GLUT1 deficiencyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011724

Submitter: G2P

GLUT1 deficiency syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000188

Submitter: ClinGen

*SLC2A1* was first reported in relation to autosomal dominant GLUT1 deficiency syndrome in 1998 (Seidner et al., PMID: 9462754). *SLC2A1* encodes GLUT1, a facilitated glucose transporter, expressed in the blood-brain barrier, placenta and erythrocytes, among other tissues. GLUT1 deficiency syndrome is characterized by reduced glucose levels in the brain and CSF (hypoglycorrhachia), intellectual deficits, seizures, movement disorders, paroxysmal exercise-induced dyskinesia, and in some cases, hemolytic anemia, cation-leaky erythrocytes, and stomatin-deficient cryohydrocytosis. In OMIM, *SLC2A1* is associated with the following disease entities: Dystonia 9 (MIM:601042), Severe infantile-onset GLUT1 deficiency syndrome 1 (MIM:606777), Childhood-onset GLUT1 deficiency syndrome 2 (MIM:612126), Stomatin-deficient cryohydrocytosis with neurologic defects (MIM:608885), and Susceptibility to idiopathic generalized epilepsy 12 (MIM:614847). In Orphanet, the gene is associated with Childhood absence epilepsy (ORPHA:64280), Encephalopathy due to GLUT1 deficiency (ORPHA:71277), Hereditary cryohydrocytosis with reduced stomatin (ORPHA:168577), Paroxysmal dystonic choreathetosis with episodic ataxia and spasticity (ORPHA:53583), and Paroxysmal exertion-induced dyskinesia (ORPHA:98811). These disorders are recognized to be part of the phenotypic spectrum associated with GLUT1 deficiency in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1430/#glut1.Nomenclature). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism or inheritance pattern, and we found that the phenotypic variability represents a spectrum. GLUT1 deficiency syndrome is known to show intrafamilial and interfamilial variability (PMIDs: 27725288, 18451999). Therefore, all of the disease entities have been lumped into one disease entity, GLUT1 deficiency syndrome (MONDO:0000188). At least 90 variants (missense, nonsense, frameshift, in-frame and out-of-frame deletion, exon and whole gene deletion) have been reported. Nine variants that have been reported in 10 probands in three publications (PMIDs: 9462754, 26193382, 18451999) are included in this curation. Variants in this gene segregated with disease in 11 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Heterozygous variants in *SLC2A1* are the predominant cause of GLUT1 deficiency syndrome. Most variants are *de novo*, but familial cases are also reported. The mechanism for disease is haploinsufficiency, causing reduced transport activity of the GLUT1 protein (PMID: 9462754). Two families with autosomal recessive inheritance have been reported, in whom the severity of the disease was determined by the degree of loss of function (PMID: 20687207) of the protein. They have not been included in this curation, however. Complete loss of function of *SLC2A1* is incompatible with life (PMID: 16497725). This gene-disease relationship is also supported by *in vitro* functional assays (PMIDs: 2348864, 10562431, 2710134), mouse models recapitulating the disease (PMIDs: 16497725, 16880609), and gene-therapy mediated rescue in mice (PMID: 28119822). In summary, there is definitive evidence supporting the relationship between *SLC2A1* and autosomal dominant GLUT1 deficiency syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 17, 2019 (SOP Version 6).

encephalopathy due to GLUT1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011724

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

GLUT1 deficiency syndrome 1; GLUT1 deficiency syndrome 2; Dystonia 9; Epilepsy, idiopathic generalized, susceptibility to, 12; Stomatin-deficient cryohydrocytosis with neurologic defectsAD/AR

Manifestation: Hematologic; Neurologic

Intervention: Hematologic; Neurologic

Rationale: Correct diagnosis is important, as ketogenic diet may result in marked clinical improvement of seizures and motor symptoms; Individuals have been described with anemia requiring transfusions; For Dystonia 9, medical management (with acetazolamide and other agents) has been described as beneficial

Refs: 1575453; 7174793; 8808284; 9462754; 10980529; 11603379; 12555938; 12548383; 15132717; 15180870; 16171377; 15622525; 18451999; 18577546; 19304421; 19630075; 19798636; 19901175; 20574033; 21791420; 21832227; 22282645; 22492876; 23280796; 26336901; 26537434; 28331464Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC2A1 variants in ClinVar

40 Conditions Cataloged
GLUT1 deficiency syndrome 1, autosomal recessiveTotal: 819
not providedTotal: 429
Encephalopathy due to GLUT1 deficiencyTotal: 298
Childhood onset GLUT1 deficiency syndrome 2Total: 200
Dystonia 9Total: 195
Epilepsy, idiopathic generalized, susceptibility to, 12Total: 168
Hereditary cryohydrocytosis with reduced stomatinTotal: 162
Inborn genetic diseasesTotal: 116

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006516.4. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
1
clinvar
11
clinvar
190
clinvar
7
clinvar
 211
missense
50
clinvar
104
clinvar
366
clinvar
24
clinvar
1
clinvar
 545
nonsense
39
clinvar
5
clinvar
 44
start loss
4
clinvar
1
clinvar
 5
frameshift
103
clinvar
12
clinvar
2
clinvar
 117
splice donor/acceptor (+/-2bp)
25
clinvar
8
clinvar
1
clinvar
 34
Total2231313802148956

Highest pathogenic variant AF is 0.000006572375

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_006516.4RefSeqNP_006507.210MANE Select
ENST00000426263.10EnsemblENSP00000416293.210MANE Select
ENST00000372500.4EnsemblENSP00000361578.43Standard
ENST00000460369.3EnsemblENSP00000491942.12Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
slc2a1bDanio rerio

Structure: dorsal longitudinal anastomotic vessel

Quality: aplastic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Adipocytokine signaling pathway - Homo sapiens (human)
  • Renal cell carcinoma - Homo sapiens (human)
  • Central carbon metabolism in cancer - Homo sapiens (human)
  • Insulin resistance - Homo sapiens (human)
  • HIF-1 signaling pathway - Homo sapiens (human)

Biological Process

  • response to hypoxia
  • lactose biosynthetic process
  • female pregnancy
  • regulation of glucose transmembrane transport
  • L-ascorbic acid metabolic process

Molecular Function

  • glucose transmembrane transporter activity
  • protein binding
  • kinase binding
  • dehydroascorbic acid transmembrane transporter activity
  • identical protein binding

Cellular Component

  • Golgi membrane
  • female pronucleus
  • cytosol
  • plasma membrane
  • integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000426263
Coding exons
10
Length
33479
Individuals with no LoFs
125742
Homozygous LoFs
0
Heterozygous LoFs
2
Defined
125744
p
0.00000795
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.931603030.5270.00002153162
Missense (PolyPhen)56152.960.366121513
Synonymous0.1161241260.9870.000008871049
Loss of Function3.90119.70.05089.45e-7221

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.00000880.0000088rare
South Asian00.0absent
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Facilitative glucose transporter. This isoform may be responsible for constitutive or basal glucose uptake. Has a very broad substrate specificity; can transport a wide range of aldoses including both pentoses and hexoses. {ECO:0000269|PubMed:18245775, ECO:0000269|PubMed:19449892}.;
Disease
DISEASE: GLUT1 deficiency syndrome 2 (GLUT1DS2) [MIM:612126]: A clinically variable disorder characterized primarily by onset in childhood of paroxysmal exercise-induced dyskinesia. The dyskinesia involves transient abnormal involuntary movements, such as dystonia and choreoathetosis, induced by exercise or exertion, and affecting the exercised limbs. Some patients may also have epilepsy, most commonly childhood absence epilepsy. Mild mental retardation may also occur. In some patients involuntary exertion- induced dystonic, choreoathetotic, and ballistic movements may be associated with macrocytic hemolytic anemia. {ECO:0000269|PubMed:14605501, ECO:0000269|PubMed:18451999, ECO:0000269|PubMed:19630075, ECO:0000269|PubMed:19798636, ECO:0000269|PubMed:20129935, ECO:0000269|PubMed:20574033, ECO:0000269|PubMed:20621801, ECO:0000269|PubMed:20830593, ECO:0000269|PubMed:21204808}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epilepsy, idiopathic generalized 12 (EIG12) [MIM:614847]: A disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. Seizure types include juvenile myoclonic seizures, absence seizures, and generalized tonic-clonic seizures. In some EIG12 patients seizures may remit with age. {ECO:0000269|PubMed:19798636, ECO:0000269|PubMed:22282645, ECO:0000269|PubMed:23280796}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Dystonia 9 (DYT9) [MIM:601042]: An autosomal dominant neurologic disorder characterized by childhood onset of paroxysmal choreoathetosis and progressive spastic paraplegia. Most patients show some degree of cognitive impairment. Other variable features may include seizures, migraine headaches, and ataxia. {ECO:0000269|PubMed:21832227}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Stomatin-deficient cryohydrocytosis with neurologic defects (SDCHCN) [MIM:608885]: A rare form of stomatocytosis characterized by episodic hemolytic anemia, cold-induced red cells cation leak, erratic hyperkalemia, neonatal hyperbilirubinemia, hepatosplenomegaly, cataracts, seizures, mental retardation, and movement disorder. {ECO:0000269|PubMed:21791420, ECO:0000269|PubMed:22492876}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.789

Intolerance Scores

LoFtool
0.0901
RVIS EVS
-1.05
RVIS percentile EVS
7.66

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
H
Indispensability pred.
E
Indispensability score
0.887

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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