Submissions for variant NM_006516.4(SLC2A1):c.998G>A (p.Arg333Gln)

dbSNP: rs1553155986

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000517267	SCV000616333	likely pathogenic	Encephalopathy due to GLUT1 deficiency	2017-10-16	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000792856	SCV000932180	pathogenic	GLUT1 deficiency syndrome 1, autosomal recessive	2023-07-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 333 of the SLC2A1 protein (p.Arg333Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GLUT1-deficiency syndrome and paroxysmal exertion induced dystonia (PMID: 19630075, 20129935, 26193382, 26598494). ClinVar contains an entry for this variant (Variation ID: 448897). 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. 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: 11477212, 21555602). 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.
CeGaT Center for Human Genetics Tuebingen	RCV001091411	SCV001247437	pathogenic	not provided	2017-08-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001091411	SCV002043960	pathogenic	not provided	2023-02-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26193382, 35146065, 24847886, 19630075, 19554569, 31302675, 32753446, 28042592)
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001814181	SCV002061835	pathogenic	Encephalopathy due to GLUT1 deficiency; Childhood onset GLUT1 deficiency syndrome 2	2021-04-20	criteria provided, single submitter	clinical testing	PS4, PP3, PM2, PM5, PM6
MGZ Medical Genetics Center	RCV002289706	SCV002580390	likely pathogenic	Childhood onset GLUT1 deficiency syndrome 2	2021-10-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000517267	SCV004172793	likely pathogenic	Encephalopathy due to GLUT1 deficiency	2023-04-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000517267	SCV004801544	pathogenic	Encephalopathy due to GLUT1 deficiency	2020-09-16	criteria provided, single submitter	clinical testing	The SLC2A1 c.998G>A p.(Arg333Gln) variant is a missense variant that has been reported in at least six unrelated individuals with glucose transporter type I (GLUT1) deficiency (Schneider et al. 2009; Leen et al. 2010; Baschieri et al. 2014; Hully et al. 2015; Gardiner et al. 2015). The clinical features described in these individuals varied and included paroxysmal exercise-induced and kinesigenic dyskinesia, GLUT1 deficiency syndrome, and late-onset classical GLUT1 deficiency syndrome. The p.(Arg333Gln) variant is absent from a region of good coverage in the Genome Aggregation Database, indicating it is rare. Arginine 333 is part of a highly conserved Arg-X-Gly-Arg-Arg motif between helices eight and nine that is believed to play an important role in the transporter's membrane topology (Sato and Mueckler 1999). Multiple individuals with a different missense change at the same position, p.(Arg333Trp), have also been reported (Hully et al. 2015; Gardner et al. 2015). Based on the collective evidence, the p.(Arg333Gln) variant is classified as pathogenic for glucose transporter type I deficiency syndrome.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000517267	SCV005398171	pathogenic	Encephalopathy due to GLUT1 deficiency	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with SLC2A1-related disorders (MIM# 614847, 601042, 606777, 612126). (I) 0108 - This gene is associated with both recessive and dominant disease. Autosomal dominant is the common mode of inheritance with rare reports of autosomal recessive inheritance (GeneReviews). (I) 0112 - The condition associated with this gene has incomplete penetrance. While penetrance is largely complete for GLUT1 deficiency syndrome, reduced penetrance has been reported for stomatin-deficient cryohydrocytosis with neurologic defects, generalized idiopathic epilepsy and a single family with GLUT1 deficiency syndrome (GeneReviews, OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Missense variants have been described to lead to a milder phenotype compared to null variants (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glucose transporter within the cytoplasmic region (DECIPHER, NCBI, Uniprot). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It’s been reported in at least nine patients with GLUT1 deficiency syndrome, including de novo events. This variant has also been classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 20129935, 24487825, 26193382, 26598494, 28042592, 32753446). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign