Submissions for variant NM_006516.4(SLC2A1):c.277C>T (p.Arg93Trp)

gnomAD frequency: 0.00001  dbSNP: rs267607061

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000442654	SCV000520908	pathogenic	not provided	2018-08-24	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000648074	SCV000769884	pathogenic	GLUT1 deficiency syndrome 1, autosomal recessive	2022-01-12	criteria provided, single submitter	clinical testing	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).
New York Genome Center	RCV001291641	SCV001480215	pathogenic	Encephalopathy due to GLUT1 deficiency	2019-09-10	criteria provided, single submitter	clinical testing	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.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001548750	SCV001763567	pathogenic	Seizure	2021-08-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549375	SCV004119138	pathogenic	SLC2A1-related disorder	2022-08-18	criteria provided, single submitter	clinical testing	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.
Genome-Nilou Lab	RCV001291641	SCV004173541	pathogenic	Encephalopathy due to GLUT1 deficiency	2023-04-11	criteria provided, single submitter	clinical testing
OMIM	RCV000030922	SCV000037769	pathogenic	Childhood onset GLUT1 deficiency syndrome 2	2009-12-08	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000442654	SCV001744513	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000442654	SCV001958727	likely pathogenic	not provided		no assertion criteria provided	clinical testing