1-42930724-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_006516.4(SLC2A1):c.418G>A(p.Val140Met) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V140L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SLC2A1
NM_006516.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 5.85

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

encephalopathy due to GLUT1 deficiency
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
GLUT1 deficiency syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
childhood onset GLUT1 deficiency syndrome 2
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
dystonia 9
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
epilepsy, idiopathic generalized, susceptibility to, 12
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
childhood absence epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary cryohydrocytosis with reduced stomatin
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
myoclonic-astatic epilepsy
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

SLC2A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr1-42930724-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2697280.Status of the report is criteria_provided_single_submitter, 1 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 epilepsy, idiopathic generalized, susceptibility to, 12, GLUT1 deficiency syndrome, encephalopathy due to GLUT1 deficiency, dystonia 9, hereditary cryohydrocytosis with reduced stomatin, childhood onset GLUT1 deficiency syndrome 2, childhood absence epilepsy, myoclonic-astatic epilepsy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.857

PP5

Variant 1-42930724-C-T is Pathogenic according to our data. Variant chr1-42930724-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 372507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC2A1	NM_006516.4 link	c.418G>A	p.Val140Met	missense_variant	Exon 4 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.418G>A	p.Val140Met	missense_variant	Exon 4 of 10	1	NM_006516.4	ENSP00000416293.2		P11166

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1459844

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726388

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51488

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111946

Other (OTH)

AF:

0.00

AC:

AN:

60380

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Aug 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 21, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect with impaired glucose uptake (Suls et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18577546, 25099510, 29356177, 30895386, 33163569, 35627257, 29655203, 28129950, 33860439) -

Encephalopathy due to GLUT1 deficiency

Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GLUT1 deficiency syndrome 1, autosomal recessive

Pathogenic:1

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 140 of the SLC2A1 protein (p.Val140Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant SLC2A1-related conditions (PMID: 18577546, 29356177, 29655203). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 372507). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SLC2A1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC2A1 function (PMID: 18577546). This variant disrupts the p.Val140 amino acid residue in SLC2A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31273778; internal data). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

D;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

D;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Uncertain

0.53

MutationAssessor

Pathogenic

3.2

M;.

PhyloP100

5.8

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.4

N;N

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

1.0

D;.

Vest4

0.82

MutPred

0.72

Loss of catalytic residue at V140 (P = 0.1847);.;

MVP

0.95

MPC

2.0

ClinPred

0.99

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.87

gMVP

0.79

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over