1-42930865-G-A
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 0.00000125 in 1,600,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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
Consequence
NM_006516.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC2A1 | NM_006516.4 | c.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 |
---|---|---|---|---|---|---|---|---|---|
SLC2A1 | ENST00000426263.10 | c.277C>T | p.Arg93Trp | missense_variant, splice_region_variant | 4/10 | 1 | NM_006516.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152118Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.90e-7 AC: 1AN: 1448682Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1AN XY: 721034
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74298
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 24, 2018 | The 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. - |
Encephalopathy due to GLUT1 deficiency Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Sep 10, 2019 | The 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. - |
SLC2A1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 18, 2022 | The 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. - |
Childhood onset GLUT1 deficiency syndrome 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 08, 2009 | - - |
GLUT1 deficiency syndrome 1, autosomal recessive Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2022 | Algorithms 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 submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | Aug 03, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at