Submissions for variant NM_006516.4(SLC2A1):c.667C>T (p.Arg223Trp)

dbSNP: rs796053248

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189355	SCV000242992	pathogenic	not provided	2022-01-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the R223W variant impairs GLUT1 phosphorylation and TPA-induced glucose transport (Lee et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26537434, 26598494, 29303961, 34135856, 28116237, 25982116, 30952489, 25564316, 24847886, 20129935, 30714351, 29655203, 30700737)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000189355	SCV000609722	pathogenic	not provided	2017-08-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000546488	SCV000649807	pathogenic	GLUT1 deficiency syndrome 1, autosomal recessive	2024-04-25	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 223 of the SLC2A1 protein (p.Arg223Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GLUT-1 deficiency related epilepsy (PMID: 20129935, 25564316, 26537434, 26598494, 28116237). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207193). 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: 25982116). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763337	SCV000894019	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
CeGaT Center for Human Genetics Tuebingen	RCV000189355	SCV001247438	pathogenic	not provided	2020-09-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288795	SCV002579957	pathogenic	Encephalopathy due to GLUT1 deficiency	2022-05-25	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288795	SCV004173348	pathogenic	Encephalopathy due to GLUT1 deficiency	2023-04-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002288795	SCV005062119	pathogenic	Encephalopathy due to GLUT1 deficiency	2024-03-04	criteria provided, single submitter	clinical testing	Variant summary: SLC2A1 c.667C>T (p.Arg223Trp) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251442 control chromosomes (gnomAD). c.667C>T has been reported in the literature in multiple individuals affected with GLUT1 Deficiency Syndrome 1 and at-least one case was reported as a De novo occurrence (examples: Leen_2010, Gardiner_2015, De Giorgis_2015, Larsen_2015, Lindy_2018, Scoppola_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20129935, 26598494, 25564316, 34135856, 26537434, 29655203). ClinVar contains an entry for this variant (Variation ID: 207193). Based on the evidence outlined above, the variant was classified as pathogenic.