rs387907313

Positions:

chr1-42929766-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_006516.4(SLC2A1):c.694C>T(p.Arg232Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R232H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC2A1
NM_006516.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 1.26

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a hotspot region, there are 3 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 chr1-42929765-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 623683.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1}.

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, 0.926

PP5

Variant 1-42929766-G-A is Pathogenic according to our data. Variant chr1-42929766-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC2A1	NM_006516.4 linkuse as main transcript	c.694C>T	p.Arg232Cys	missense_variant	6/10	ENST00000426263.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC2A1	ENST00000426263.10 linkuse as main transcript	c.694C>T	p.Arg232Cys	missense_variant	6/10	1	NM_006516.4	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251426

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

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.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2014	p.Arg232Cys (CGC>TGC): c.694 C>T in exon 6 of the SLC2A1 gene (NM_006516.2)The R232C mutation in the SLC2A1 gene was previously reported in multiple individuals from one family with idiopathic generalized epilepsy, predominantly characterized by absence seizures, and it was also detected in several unaffected family members consistent with reduced penetrance for this mutation (Striano et al., 2012). Functional studies indicate this mutation mildly impairs glucose transport (Striano et al., 2012). R232C was not detected in 846 normal control individuals, and the NHLBI ESP Exome Variant Project has not identified it in approximately 6,500 individuals of European or African American ethnicity (Striano et al., 2012; Exome Variant Project, 2014). The R232C mutation results in a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and in silico algorithms predict R232C may be damaging to protein structure and function. It alters a highly conserved residue in the cytoplasmic loop between the sixth and seventh transmembrane domains, and missense mutations have been reported at other residues in this region of the protein in association with GLUT1 deficiency (Leen et al., 2010). The variant is found in EPILEPSY,CHILD-EPI panel(s). -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -

Encephalopathy due to GLUT1 deficiency

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

GLUT1 deficiency syndrome 1, autosomal recessive

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 15, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC2A1 function (PMID: 22282645). 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. ClinVar contains an entry for this variant (Variation ID: 37301). This missense change has been observed in individual(s) with idiopathic generalized epilepsy (PMID: 22282645; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs387907313, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 232 of the SLC2A1 protein (p.Arg232Cys). -

Epilepsy, idiopathic generalized, susceptibility to, 12

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Feb 21, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.55

MutationAssessor

Pathogenic

3.6

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-5.3

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.93

MutPred

0.69

Loss of MoRF binding (P = 0.0016);

MVP

0.95

MPC

2.3

ClinPred

0.99

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.83

gMVP

0.85

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

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