rs202060209

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_006516.4(SLC2A1):c.274C>T(p.Arg92Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R92Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

SLC2A1
NM_006516.4 missense, splice_region

Scores

Splicing: ADA: 0.0004506

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 1.41

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 17 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_006516.4

PM2

Very rare variant in population databases, with high coverage;

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, 0.989

PP5

Variant 1-42931047-G-A is Pathogenic according to our data. Variant chr1-42931047-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-42931047-G-A is described in Lovd as [Pathogenic]. Variant chr1-42931047-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC2A1	NM_006516.4 link	c.274C>T	p.Arg92Trp	missense_variant, splice_region_variant	Exon 3 of 10	ENST00000426263.10	NP_006507.2	P11166Q59GX2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC2A1	ENST00000426263.10 link	c.274C>T	p.Arg92Trp	missense_variant, splice_region_variant	Exon 3 of 10	1	NM_006516.4	ENSP00000416293.2		P11166

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SLC2A1: PP1:Strong, PS2, PM2, PS4:Moderate, PP3 -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 30, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 26598494, 24892788, 24847886, 19630075, 26350204, 32247176, 31440721, 25564316) -

Developmental disorder

Pathogenic:1

Nov 19, 2021

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Encephalopathy due to GLUT1 deficiency

Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Childhood onset GLUT1 deficiency syndrome 2

Pathogenic:1

Aug 15, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

GLUT1 deficiency syndrome 1, autosomal recessive

Pathogenic:1

Oct 17, 2024

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 92 of the SLC2A1 protein (p.Arg92Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PED and paroxysmal kinesigenic dyskinesia (PKD) and paroxysmal exercise-induced dyskinesia (PED) and GLUT1 deficiency syndrome (PMID: 19630075, 25564316, 26598494). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 16119). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Intellectual disability

Pathogenic:1

Feb 13, 2019

Raymond Lab, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Childhood onset GLUT1 deficiency syndrome 2;C4551966:Encephalopathy due to GLUT1 deficiency

Pathogenic:1

May 13, 2022

Laboratory of Human Genetics, Universidade de São Paulo

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This variant meets our criteria to be classified as pathogenic based upon segregation studies, extremely low frequency, and in-silico evaluation of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

D;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Benign

0.65

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Pathogenic

4.6

H;.

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-7.0

D;.

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.99

MutPred

0.95

Loss of methylation at R92 (P = 0.0185);.;

MVP

1.0

MPC

2.1

ClinPred

0.99

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.94

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00045

dbscSNV1_RF

Benign

0.18

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

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