rs80359825

Variant names:

• chr1-42929009-G-A
• rs80359825
• NM_006516.4:c.997C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-42929009-G-A
• chr1-42929009-G-C
• chr1-42929009-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_006516.4(SLC2A1):​c.997C>T​(p.Arg333Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R333Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC2A1 NM_006516.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 6.29

Genes affected

SLC2A1 (HGNC:11005): (solute carrier family 2 member 1) 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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 uncertain in NM_006516.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-42929008-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 448897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the SLC2A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 98 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 2.9256 (below the threshold of 3.09). Trascript score misZ: 4.6729 (above the threshold of 3.09). GenCC associations: The gene is linked to childhood absence epilepsy, dystonia 9, epilepsy, idiopathic generalized, susceptibility to, 12, GLUT1 deficiency syndrome, myoclonic-astatic epilepsy, childhood onset GLUT1 deficiency syndrome 2, hereditary cryohydrocytosis with reduced stomatin, encephalopathy due to GLUT1 deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 1-42929009-G-A is Pathogenic according to our data. Variant chr1-42929009-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 198842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-42929009-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC2A1	NM_006516.4	c.997C>T	p.Arg333Trp	missense_variant	Exon 8 of 10	ENST00000426263.10	NP_006507.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC2A1	ENST00000426263.10	c.997C>T	p.Arg333Trp	missense_variant	Exon 8 of 10	1	NM_006516.4	ENSP00000416293.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Aug 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 18, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate this variant severely reduces Glut1 mediated glucose transport activity (Wong et al., 2007); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29778030, 21555602, 21069159, 24847886, 11477212, 10980529, 29892515, 30198221, 29056246, 30824189, 31130284, 32655480, 32025761, 32712428, 34489640, 31069529, 17052934) -

Aug 29, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Encephalopathy due to GLUT1 deficiency Pathogenic:1 Other:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dystonia 9 Pathogenic:1

Jul 07, 2023

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Apr 18, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R333W pathogenic mutation (also known as c.997C>T), located in coding exon 8 of the SLC2A1 gene, results from a C to T substitution at nucleotide position 997. The arginine at codon 333 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in multiple individuals with clinical diagnoses of GLUT1 deficiency syndrome with a spectrum of severity of disease (Ho YY et al. Pediatr Res. 2001 Aug; 50(2):254-60; Fujii T et al. Brain Dev. 2007 Mar; 29(2):92-7; Ramm-Pettersen ;A et al. Dev Med Child Neurol. 2013 May; 55(5):440-7; Ito Y et al. Brain Dev. 2015 Sep; 37(8):780-9); additionally, the mutation was reportedly de novo in some patients (Fung EL et al. Brain Dev. 2011 Feb; 33(2):170-3; Mullen SA et al. Arch Neurol. 2011 Sep; 68(9):1152-5). Functional studies on patient cells and in vitro found this mutation resulted in significantly decreased glucose uptake (Wang D et al. Hum Mutat. 2000 Sep;16(3):224-31; Wong HY et al. Mol Genet Metab. 2007 Feb; 90(2):193-8). Based on the supporting evidence, p.R333W is interpreted as a disease-causing mutation. -

Childhood onset GLUT1 deficiency syndrome 2 Pathogenic:1

Jun 10, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GLUT1 deficiency syndrome 1, autosomal recessive Pathogenic:1

Oct 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 333 of the SLC2A1 protein (p.Arg333Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glucose transporter type 1 deficiency syndrome (PMID: 10980529, 11477212, 21555602). In at least one individual the variant was observed to be de novo. This variant is also known as c.1176C>T. ClinVar contains an entry for this variant (Variation ID: 198842). 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 with a positive predictive value of 95%. 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: 19630075, 20129935, 26193382, 26598494). 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. -

GLUT1 deficiency syndrome Pathogenic:1

Nov 04, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dystonia 9;C1837206:Hereditary cryohydrocytosis with reduced stomatin;C1842534:Childhood onset GLUT1 deficiency syndrome 2;C3553859:Epilepsy, idiopathic generalized, susceptibility to, 12;C4551966:Encephalopathy due to GLUT1 deficiency Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.97		Loss of methylation at R333 (P = 0.032);
MVP		0.97
MPC		2.1
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.7
Varity_R		0.97
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80359825; hg19: chr1-43394680;