Variant rs796053248 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong

The NM_006516.4(SLC2A1):c.667C>T(p.Arg223Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R223Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC2A1
NM_006516.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 4.44

Variant links:

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]

SLC2A1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SLC2A1. . Gene score misZ 2.9256 (greater than the threshold 3.09). Trascript score misZ 4.6729 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.87

PP5

Variant 1-42929885-G-A is Pathogenic according to our data. Variant chr1-42929885-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 207193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC2A1	NM_006516.4 linkuse as main transcript	c.667C>T	p.Arg223Trp	missense_variant	5/10	ENST00000426263.10	NP_006507.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC2A1	ENST00000426263.10 linkuse as main transcript	c.667C>T	p.Arg223Trp	missense_variant	5/10	1	NM_006516.4	ENSP00000416293	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Encephalopathy due to GLUT1 deficiency

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 04, 2024	Variant summary: SLC2A1 c.667C>T (p.Arg223Trp) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251442 control chromosomes (gnomAD). c.667C>T has been reported in the literature in multiple individuals affected with GLUT1 Deficiency Syndrome 1 and at-least one case was reported as a De novo occurrence (examples: Leen_2010, Gardiner_2015, De Giorgis_2015, Larsen_2015, Lindy_2018, Scoppola_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20129935, 26598494, 25564316, 34135856, 26537434, 29655203). ClinVar contains an entry for this variant (Variation ID: 207193). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2022	Published functional studies demonstrate the R223W variant impairs GLUT1 phosphorylation and TPA-induced glucose transport (Lee et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26537434, 26598494, 29303961, 34135856, 28116237, 25982116, 30952489, 25564316, 24847886, 20129935, 30714351, 29655203, 30700737) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 10, 2017	- -

GLUT1 deficiency syndrome 1, autosomal recessive

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 08, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 223 of the SLC2A1 protein (p.Arg223Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GLUT-1 deficiency related epilepsy (PMID: 20129935, 25564316, 26537434, 26598494, 28116237). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207193). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt SLC2A1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC2A1 function (PMID: 25982116). For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.87

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

1.8

MutationTaster

Benign

0.95

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.61

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

0.99

Vest4

0.83

MutPred

0.58

Loss of disorder (P = 0.0058);

MVP

0.87

MPC

1.9

ClinPred

0.98

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.73

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over