Submissions for variant NM_006516.4(SLC2A1):c.376C>T (p.Arg126Cys)

dbSNP: rs80359818

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000081431	SCV000230326	pathogenic	not provided	2013-06-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000081431	SCV000242987	pathogenic	not provided	2023-08-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect by significantly impairing glucose transport (Wong et al., 2007; Suls et al., 2009; Zaman et al., 2018); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19798636, 21546317, 17052934, 24847886, 27725288, 28717674, 12325075, 30588498, 29530121, 29655203, 31352161, 31440721, 28116237)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000546969	SCV000649804	pathogenic	GLUT1 deficiency syndrome 1, autosomal recessive	2024-02-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 126 of the SLC2A1 protein (p.Arg126Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant GLUT1 deficiency syndrome (PMID: 17718830, 21546317, 26193382). ClinVar contains an entry for this variant (Variation ID: 16118). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt SLC2A1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC2A1 function (PMID: 17052934, 19798636). This variant disrupts the p.Arg126 amino acid residue in SLC2A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17718830, 19798636, 26193382). 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.
Baylor Genetics	RCV000017498	SCV000807597	pathogenic	Encephalopathy due to GLUT1 deficiency	2017-09-01	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 3-year-old female with static encephalopathy, developmental delay, hypotonia, seizures
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000824987	SCV000966167	likely pathogenic	Hereditary cryohydrocytosis with reduced stomatin	2018-10-19	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000824987	SCV001440847	pathogenic	Hereditary cryohydrocytosis with reduced stomatin	2019-01-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000017498	SCV004173482	likely pathogenic	Encephalopathy due to GLUT1 deficiency	2023-04-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000081431	SCV004704287	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	SLC2A1: PM1, PM2, PM5, PS4:Moderate, PP3, PS2:Supporting, PS3:Supporting
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV004791223	SCV005413141	pathogenic	Chromosome 17q23.1-q23.2 deletion syndrome	2024-07-17	criteria provided, single submitter	clinical testing
OMIM	RCV000017498	SCV000037770	pathogenic	Encephalopathy due to GLUT1 deficiency	2011-09-06	no assertion criteria provided	literature only
OMIM	RCV000030838	SCV000053513	pathogenic	Childhood onset GLUT1 deficiency syndrome 2	2011-09-06	no assertion criteria provided	literature only
OMIM	RCV000030839	SCV000053514	pathogenic	Dystonia 9	2011-09-06	no assertion criteria provided	literature only
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV000017498	SCV001738760	pathogenic	Encephalopathy due to GLUT1 deficiency	2020-01-01	no assertion criteria provided	clinical testing
GeneReviews	RCV000017498	SCV002556351	not provided	Encephalopathy due to GLUT1 deficiency		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004737154	SCV005358969	pathogenic	SLC2A1-related disorder	2024-06-13	no assertion criteria provided	clinical testing	The SLC2A1 c.376C>T variant is predicted to result in the amino acid substitution p.Arg126Cys. This variant has been reported in individuals with autosomal dominant glucose transporter type 1 deficiency syndrome (for examples, see Pascual et al. 2002. PubMed ID: 12325075; Suls et al. 2009. PubMed ID: 19798636; Gökben et al. 2011. PubMed ID: 21546317; Diomedi et al. 2016. PubMed ID: 27725288; Lindy et al. 2018. PubMed ID: 29655203; Zaman et al. 2018. PubMed ID: 30588498; Madaan et al. 2019. PubMed ID: 31352161). Of note, other missense variants (p.Arg126His and p.Arg126Leu), affecting the same amino acid, have also been causative for glucose transporter type 1 deficiency syndrome (Human Gene Mutation Database; https://www.hgmd.cf.ac.uk/). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.