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rs267607061

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_006516.4(SLC2A1):c.277C>T(p.Arg93Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000203 in 985,226 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. R93Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000012 ( 0 hom. )

Consequence

SLC2A1
NM_006516.4 missense, splice_region

Scores

11
7
1
Splicing: ADA: 0.9721
1
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 2.92
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]

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ACMG classification

Classification made for transcript

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 0 benign, 8 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 chr1-42930864-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 623684.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1, Pathogenic=1}.
PP2
Missense variant where missense usually causes diseases, SLC2A1
PP3
MetaRNN computational evidence supports a deleterious effect, 0.944
PP5
Variant 1-42930865-G-A is Pathogenic according to our data. Variant chr1-42930865-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-42930865-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-42930865-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC2A1NM_006516.4 linkuse as main transcriptc.277C>T p.Arg93Trp missense_variant, splice_region_variant 4/10 ENST00000426263.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC2A1ENST00000426263.10 linkuse as main transcriptc.277C>T p.Arg93Trp missense_variant, splice_region_variant 4/101 NM_006516.4 P1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152118
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000943
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000120
AC:
1
AN:
833108
Hom.:
0
Cov.:
33
AF XY:
0.00000260
AC XY:
1
AN XY:
384714
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:
0.00000131
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152118
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74298
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000943
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingGeneDxAug 24, 2018The R93W variant in the SLC2A1 gene has been reported previously in multiple unrelated individuals with glucose transporter type 1 deficiency syndrome (Glut1-DS) (Rotstein et al., 2009; Leen et al., 2010). The R93W variant is not observed in large population cohorts (Lek et al., 2016). The R93W variant is 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. Functional studies suggest that the R93W variant results in reduced glucose uptake (Pascual et al., 2008). We interpret R93W as a pathogenic variant. -
Likely pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Encephalopathy due to GLUT1 deficiency Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Pathogenic, criteria provided, single submitterclinical testingNew York Genome CenterSep 10, 2019The variant c.277C>T, p.Arg93Trp has been reported in multiple individuals with GLUT1 deficiency syndrome [MIM#606777] [PMID: 24847886; PMID: 2344855; PMID:23106342; PMID: 19996082]. This mutation is located in the first cytosolic loop of the protein [PMID: 19996082]. The variant has 0.003% allele frequency in the gnomAD database (1 out of 31,368 heterozygous alleles) indicating this is a rare variant and in silico tool predicts the variant is expected to be deleterious. Functional studies suggest that the variant results in reduced glucose uptake [PMID: 18387950]. Based on the available evidence, the variant c.277C>T, p.Arg93Trp in the SLC2A1 gene is classified as pathogenic. -
Childhood onset GLUT1 deficiency syndrome 2 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 08, 2009- -
SLC2A1-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesAug 18, 2022The SLC2A1 c.277C>T variant is predicted to result in the amino acid substitution p.Arg93Trp. This variant has been reported in multiple individuals with GLUT1 deficiency (Joshi et al. 2008. PubMed ID: 18403583; Arsov et al. 2012. PubMed ID: 23106342; Ramm-Pettersen et al. 2013. PubMed ID: 23448551; Supplemental Table for Symonds et al. 2019. PubMed ID: 31302675) and an individual with alternating hemiplegia of childhood (Rotstein et al, 2009. PubMed ID: 19996082). An alternate substitution of the same amino acid has also been reported in association with GLUT1 deficiency (Magrinelli et al. 2020. PubMed ID: 32753446). In a functional study, the p.Arg93Trp substitution was reported to reduce glucose transport in erythrocytes (Pascual et al. 2008. PubMed ID: 18387950) This variant is reported in 0.029% of alleles in individuals of European (Finnish) descent in gnomAD (1 of 31,368 total alleles in http://gnomad.broadinstitute.org/variant/1-43396536-G-A). This variant is interpreted as pathogenic or likely pathogenic by multiple independent submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/16117). Based on the collective evidence, this variant is interpreted as pathogenic. -
GLUT1 deficiency syndrome 1, autosomal recessive Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 12, 2022Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 16117). This missense change has been observed in individual(s) with low cerebral spinal fluid blood glucose concentrations, findings that are highly specific for GLUT1 deficiency syndrome (PMID: 18403583, 19996082, 20129935, 23106342, 23448551). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 93 of the SLC2A1 protein (p.Arg93Trp). -
Seizure Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGénétique des Maladies du Développement, Hospices Civils de LyonAug 03, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.32
Cadd
Pathogenic
31
Dann
Pathogenic
1.0
DEOGEN2
Pathogenic
0.93
D;.
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Uncertain
0.22
D
MetaRNN
Pathogenic
0.94
D;D
MetaSVM
Uncertain
0.64
D
MutationAssessor
Pathogenic
3.8
H;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-5.2
D;.
REVEL
Pathogenic
0.74
Sift
Uncertain
0.0060
D;.
Sift4G
Uncertain
0.0050
D;D
Polyphen
1.0
D;.
Vest4
0.96
MutPred
0.75
Gain of catalytic residue at M96 (P = 0.0048);.;
MVP
0.95
MPC
2.1
ClinPred
1.0
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.86
gMVP
0.87

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.97
dbscSNV1_RF
Benign
0.68
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.

Other links and lift over

dbSNP: rs267607061; hg19: chr1-43396536; API