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NM_006516.4(SLC2A1):c.998G>A (p.Arg333Gln) AND Encephalopathy due to GLUT1 deficiency

Germline classification:
Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:
Apr 11, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000517267.5

Allele description [Variation Report for NM_006516.4(SLC2A1):c.998G>A (p.Arg333Gln)]

NM_006516.4(SLC2A1):c.998G>A (p.Arg333Gln)

Gene:
SLC2A1:solute carrier family 2 member 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p34.2
Genomic location:
Preferred name:
NM_006516.4(SLC2A1):c.998G>A (p.Arg333Gln)
HGVS:
  • NC_000001.11:g.42929008C>T
  • NG_008232.1:g.35169G>A
  • NM_006516.4:c.998G>AMANE SELECT
  • NP_006507.2:p.Arg333Gln
  • LRG_1132t1:c.998G>A
  • LRG_1132:g.35169G>A
  • NC_000001.10:g.43394679C>T
  • NM_006516.2:c.998G>A
  • NM_006516.3:c.998G>A
Protein change:
R333Q
Links:
dbSNP: rs1553155986
NCBI 1000 Genomes Browser:
rs1553155986
Molecular consequence:
  • NM_006516.4:c.998G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Encephalopathy due to GLUT1 deficiency
Synonyms:
GLUCOSE TRANSPORT DEFECT, BLOOD-BRAIN BARRIER; De Vivo disease; Glucose transporter protein syndrome; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0011724; MedGen: C4551966; Orphanet: 71277; OMIM: 606777

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000616333HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
criteria provided, single submitter

(HA_PGEN_assertions_20170620)
Likely pathogenic
(Oct 16, 2017)
unknownresearch

Citation Link,

SCV004172793Genome-Nilou Lab
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Apr 11, 2023)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004801544Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSLVariantClassificationCriteria RUGD 01 April 2020)
Pathogenic
(Sep 16, 2020)
unknownclinical testing

Citation Link,

SCV005398171Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Feb 2, 2022)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing
not providedunknownyes1not providednot provided1not providedresearch
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder.

Leen WG, Klepper J, Verbeek MM, Leferink M, Hofste T, van Engelen BG, Wevers RA, Arthur T, Bahi-Buisson N, Ballhausen D, Bekhof J, van Bogaert P, Carrilho I, Chabrol B, Champion MP, Coldwell J, Clayton P, Donner E, Evangeliou A, Ebinger F, Farrell K, Forsyth RJ, et al.

Brain. 2010 Mar;133(Pt 3):655-70. doi: 10.1093/brain/awp336. Epub 2010 Feb 2.

PubMed [citation]
PMID:
20129935

Paroxysmal exercise-induced dystonia due to GLUT1 mutation can be responsive to levodopa: a case report.

Baschieri F, Batla A, Erro R, Ganos C, Cordivari C, Bhatia KP.

J Neurol. 2014 Mar;261(3):615-6. doi: 10.1007/s00415-014-7250-x. Epub 2014 Feb 2. No abstract available.

PubMed [citation]
PMID:
24487825
See all PubMed Citations (7)

Details of each submission

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology, SCV000616333.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedresearchnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyes1not providednot provided1not providednot providednot provided

From Genome-Nilou Lab, SCV004172793.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

From Illumina Laboratory Services, Illumina, SCV004801544.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The SLC2A1 c.998G>A p.(Arg333Gln) variant is a missense variant that has been reported in at least six unrelated individuals with glucose transporter type I (GLUT1) deficiency (Schneider et al. 2009; Leen et al. 2010; Baschieri et al. 2014; Hully et al. 2015; Gardiner et al. 2015). The clinical features described in these individuals varied and included paroxysmal exercise-induced and kinesigenic dyskinesia, GLUT1 deficiency syndrome, and late-onset classical GLUT1 deficiency syndrome. The p.(Arg333Gln) variant is absent from a region of good coverage in the Genome Aggregation Database, indicating it is rare. Arginine 333 is part of a highly conserved Arg-X-Gly-Arg-Arg motif between helices eight and nine that is believed to play an important role in the transporter's membrane topology (Sato and Mueckler 1999). Multiple individuals with a different missense change at the same position, p.(Arg333Trp), have also been reported (Hully et al. 2015; Gardner et al. 2015). Based on the collective evidence, the p.(Arg333Gln) variant is classified as pathogenic for glucose transporter type I deficiency syndrome.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005398171.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with SLC2A1-related disorders (MIM# 614847, 601042, 606777, 612126). (I) 0108 - This gene is associated with both recessive and dominant disease. Autosomal dominant is the common mode of inheritance with rare reports of autosomal recessive inheritance (GeneReviews). (I) 0112 - The condition associated with this gene has incomplete penetrance. While penetrance is largely complete for GLUT1 deficiency syndrome, reduced penetrance has been reported for stomatin-deficient cryohydrocytosis with neurologic defects, generalized idiopathic epilepsy and a single family with GLUT1 deficiency syndrome (GeneReviews, OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Missense variants have been described to lead to a milder phenotype compared to null variants (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glucose transporter within the cytoplasmic region (DECIPHER, NCBI, Uniprot). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It’s been reported in at least nine patients with GLUT1 deficiency syndrome, including de novo events. This variant has also been classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 20129935, 24487825, 26193382, 26598494, 28042592, 32753446). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jan 13, 2025