Submissions for variant NM_006516.4(SLC2A1):c.884C>T (p.Thr295Met)

dbSNP: rs80359823

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189397	SCV000243035	pathogenic	not provided	2024-11-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on glucose transport activity (PMID: 17052934, 18614966, 24847886); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21546317, 20630673, 22011817, 20830593, 23740044, 18614966, 24847886, 21649651, 19798636, 16949238, 21382692, 23280796, 25487684, 17718830, 22190371, 25982116, 20186957, 29303961, 28556183, 29655203, 32005694, 32591173, 36362347, 15622525, 17052934)
Genetic Services Laboratory, University of Chicago	RCV000193872	SCV000248915	pathogenic	Encephalopathy due to GLUT1 deficiency	2015-06-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380032	SCV001577959	pathogenic	GLUT1 deficiency syndrome 1, autosomal recessive	2024-08-05	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 295 of the SLC2A1 protein (p.Thr295Met). 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: 15622525, 16949238, 20630673). In at least one individual the variant was observed to be de novo. This variant is also known as 1063C>T. ClinVar contains an entry for this variant (Variation ID: 207229). 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%. Experimental studies have shown that this missense change affects SLC2A1 function (PMID: 17052934, 18614966). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272166	SCV002558031	pathogenic	GLUT1 deficiency syndrome	2021-05-06	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 disease (OMIM), including GLUT1 deficiency syndrome (MIM# 606777). (I) 0107 - This gene is associated with autosomal dominant disease. Most individuals have autosomal dominant disease, but rare cases are described with an autosomal recessive mode of inheritance (PMID: 31196579). (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete penetrance has been reported in families with GLUT1 deficiency syndrome or epilepsy, who were heterozygous for pathogenic missense variants (OMIM, PMID:18451999). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20129935). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (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 extracellular loop between transmembrane domains 7 and 8 (PMID: 15622525). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed in multiple heterozygous patients with either GLUT1 deficiency, episodic ataxia or paroxysmal exercise-induced dyskinesia (ClinVar, LOVD, PMID: 29930392, PMID: 33015236, PMID: 15622525, PMID: 26598494). In one of these individuals, the variant had arisen de novo (PMID: 15622525). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected CHO cells have demonstrated that this variant results in protein mislocalisation, and significantly impaired glucose transport activity (PMID: 17052934). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genome-Nilou Lab	RCV000193872	SCV004172890	pathogenic	Encephalopathy due to GLUT1 deficiency	2023-04-11	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000189397	SCV004225824	pathogenic	not provided	2023-03-14	criteria provided, single submitter	clinical testing	PP1, PP3, PP4, PM1, PM2, PM5, PM6, PS3, PS4
CeGaT Center for Human Genetics Tuebingen	RCV000189397	SCV005894353	pathogenic	not provided	2024-12-01	criteria provided, single submitter	clinical testing	SLC2A1: PM1, PM2, PM5, PS2:Moderate, PS4:Moderate, PS3:Supporting
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000189397	SCV001809757	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000189397	SCV001958667	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV000193872	SCV002556356	not provided	Encephalopathy due to GLUT1 deficiency		no assertion provided	literature only