ClinVar Genomic variation as it relates to human health
NM_006516.4(SLC2A1):c.998G>A (p.Arg333Gln)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006516.4(SLC2A1):c.998G>A (p.Arg333Gln)
Variation ID: 448897 Accession: VCV000448897.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.2 1: 42929008 (GRCh38) [ NCBI UCSC ] 1: 43394679 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 19, 2017 Dec 22, 2024 Jul 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006516.4:c.998G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006507.2:p.Arg333Gln missense NC_000001.11:g.42929008C>T NC_000001.10:g.43394679C>T NG_008232.1:g.35169G>A LRG_1132:g.35169G>A LRG_1132t1:c.998G>A - Protein change
- R333Q
- Other names
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- Canonical SPDI
- NC_000001.11:42929007:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SLC2A1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1070 | 1111 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2023 | RCV000517267.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 16, 2023 | RCV000792856.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 20, 2021 | RCV001814181.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 21, 2023 | RCV001091411.25 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 4, 2021 | RCV002289706.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Oct 16, 2017)
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criteria provided, single submitter
Method: research
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Encephalopathy due to GLUT1 deficiency
Affected status: yes
Allele origin:
unknown
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Accession: SCV000616333.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Number of individuals with the variant: 1
Clinical Features:
Cleft lip (present) , Cleft palate (present) , Otitis media (present)
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Pathogenic
(Apr 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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Encephalopathy due to GLUT1 deficiency
Childhood onset GLUT1 deficiency syndrome 2
Affected status: yes
Allele origin:
germline
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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002061835.2
First in ClinVar: Jan 22, 2022 Last updated: Feb 11, 2022 |
Comment:
PS4, PP3, PM2, PM5, PM6
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Likely pathogenic
(Oct 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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Childhood onset GLUT1 deficiency syndrome 2
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580390.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4_MOD, PM1, PM5, PM6, PM2_SUP, PP3
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Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Feb 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002043960.2
First in ClinVar: Jan 01, 2022 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26193382, 35146065, 24847886, 19630075, 19554569, 31302675, 32753446, 28042592) (less)
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Pathogenic
(Jul 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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GLUT1 deficiency syndrome 1, autosomal recessive
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000932180.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 333 of the SLC2A1 protein (p.Arg333Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 333 of the SLC2A1 protein (p.Arg333Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GLUT1-deficiency syndrome and paroxysmal exertion induced dystonia (PMID: 19630075, 20129935, 26193382, 26598494). ClinVar contains an entry for this variant (Variation ID: 448897). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC2A1 protein function. This variant disrupts the p.Arg333 amino acid residue in SLC2A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11477212, 21555602). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247437.27
First in ClinVar: May 12, 2020 Last updated: Dec 22, 2024 |
Number of individuals with the variant: 1
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Likely pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Encephalopathy due to GLUT1 deficiency
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004172793.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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Pathogenic
(Sep 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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Encephalopathy due to GLUT1 deficiency
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV004801544.1
First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024 |
Comment:
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) … (more)
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. (less)
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Encephalopathy due to GLUT1 deficiency
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005398171.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
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 … (more)
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 (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Criss-cross gait: A clue to glucose transporter type 1 deficiency syndrome. | Magrinelli F | Neurology | 2020 | PMID: 32753446 |
Paroxysmal Nonepileptic Events in Glut1 Deficiency. | Klepper J | Movement disorders clinical practice | 2016 | PMID: 28042592 |
The clinical and genetic heterogeneity of paroxysmal dyskinesias. | Gardiner AR | Brain : a journal of neurology | 2015 | PMID: 26598494 |
From splitting GLUT1 deficiency syndromes to overlapping phenotypes. | Hully M | European journal of medical genetics | 2015 | PMID: 26193382 |
Paroxysmal exercise-induced dystonia due to GLUT1 mutation can be responsive to levodopa: a case report. | Baschieri F | Journal of neurology | 2014 | PMID: 24487825 |
Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. | Mullen SA | Archives of neurology | 2011 | PMID: 21555602 |
Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. | Leen WG | Brain : a journal of neurology | 2010 | PMID: 20129935 |
GLUT1 gene mutations cause sporadic paroxysmal exercise-induced dyskinesias. | Schneider SA | Movement disorders : official journal of the Movement Disorder Society | 2009 | PMID: 19630075 |
Glucose transporter type 1 deficiency syndrome (Glut1DS): methylxanthines potentiate GLUT1 haploinsufficiency in vitro. | Ho YY | Pediatric research | 2001 | PMID: 11477212 |
Text-mined citations for rs1553155986 ...
HelpRecord last updated Jan 13, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.