Submissions for variant NM_006516.4(SLC2A1):c.997C>T (p.Arg333Trp)

dbSNP: rs80359825

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000180300	SCV000232708	pathogenic	not provided	2014-08-29	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000500584	SCV000597092	likely pathogenic	GLUT1 deficiency syndrome	2015-11-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002312729	SCV000846258	pathogenic	Inborn genetic diseases	2016-04-18	criteria provided, single submitter	clinical testing	The p.R333W pathogenic mutation (also known as c.997C>T), located in coding exon 8 of the SLC2A1 gene, results from a C to T substitution at nucleotide position 997. The arginine at codon 333 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in multiple individuals with clinical diagnoses of GLUT1 deficiency syndrome with a spectrum of severity of disease (Ho YY et al. Pediatr Res. 2001 Aug; 50(2):254-60; Fujii T et al. Brain Dev. 2007 Mar; 29(2):92-7; Ramm-Pettersen ;A et al. Dev Med Child Neurol. 2013 May; 55(5):440-7; Ito Y et al. Brain Dev. 2015 Sep; 37(8):780-9); additionally, the mutation was reportedly de novo in some patients (Fung EL et al. Brain Dev. 2011 Feb; 33(2):170-3; Mullen SA et al. Arch Neurol. 2011 Sep; 68(9):1152-5). Functional studies on patient cells and in vitro found this mutation resulted in significantly decreased glucose uptake (Wang D et al. Hum Mutat. 2000 Sep;16(3):224-31; Wong HY et al. Mol Genet Metab. 2007 Feb; 90(2):193-8). Based on the supporting evidence, p.R333W is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV000763336	SCV000894018	pathogenic	Hereditary cryohydrocytosis with reduced stomatin; Dystonia 9; Encephalopathy due to GLUT1 deficiency; Childhood onset GLUT1 deficiency syndrome 2; Epilepsy, idiopathic generalized, susceptibility to, 12	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001390266	SCV001591943	pathogenic	GLUT1 deficiency syndrome 1, autosomal recessive	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 333 of the SLC2A1 protein (p.Arg333Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glucose transporter type 1 deficiency syndrome (PMID: 10980529, 11477212, 21555602). In at least one individual the variant was observed to be de novo. This variant is also known as c.1176C>T. ClinVar contains an entry for this variant (Variation ID: 198842). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg333 amino acid residue in SLC2A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19630075, 20129935, 26193382, 26598494). 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.
GeneDx	RCV000180300	SCV001768348	pathogenic	not provided	2023-04-18	criteria provided, single submitter	clinical testing	Published functional studies demonstrate this variant severely reduces Glut1 mediated glucose transport activity (Wong et al., 2007); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29778030, 21555602, 21069159, 24847886, 11477212, 10980529, 29892515, 30198221, 29056246, 30824189, 31130284, 32655480, 32025761, 32712428, 34489640, 31069529, 17052934)
CeGaT Center for Human Genetics Tuebingen	RCV000180300	SCV001961100	pathogenic	not provided	2021-08-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288787	SCV002580044	pathogenic	Childhood onset GLUT1 deficiency syndrome 2	2022-06-10	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV003335179	SCV004045851	pathogenic	Dystonia 9	2023-07-07	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002271990	SCV004172794	likely pathogenic	Encephalopathy due to GLUT1 deficiency	2023-04-11	criteria provided, single submitter	clinical testing
GeneReviews	RCV002271990	SCV002556355	not provided	Encephalopathy due to GLUT1 deficiency		no assertion provided	literature only