Submissions for variant NM_006516.4(SLC2A1):c.125A>C (p.Glu42Ala)

gnomAD frequency: 0.00004  dbSNP: rs748082803

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189348	SCV000242983	uncertain significance	not provided	2017-07-27	criteria provided, single submitter	clinical testing	p.Glu42Ala (E42A) GAG>GCG: c.125 A>C in exon 3 of the SLC2A1 gene (NM_006516.2)TThe E42A variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E42A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position conserved in mammals in the extracellular loop between the first and second transmembrane domains. Nonsense mutations at the same residue (E42X) and in a nearby residue (Q46X), as well as a nearby missense mutation (E41K), have been reported in association with glucose transporter-1 deficiency syndrome (Leen et al., 2010), supporting the functional importance of this region of the protein. However, in silico analysis predicts the E42A variant likely does not alter the protein structure/function. The possibility that it is a disease associated mutation cannot be excluded since some individuals with SLC2A1 mutations have been reported to be mildly affected or unaffected due to variability in phenotypic expression and/or reduced penetrance (Weber et al., 2008; Suls et al., 2008). The variant is found in INFANT-EPI panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000819050	SCV000959692	uncertain significance	GLUT1 deficiency syndrome 1, autosomal recessive	2023-10-09	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 42 of the SLC2A1 protein (p.Glu42Ala). This variant is present in population databases (rs748082803, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with SLC2A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 207186). 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 not expected to disrupt SLC2A1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV000189348	SCV001147241	uncertain significance	not provided	2024-06-01	criteria provided, single submitter	clinical testing	SLC2A1: PM2:Supporting, BP4
Illumina Laboratory Services, Illumina	RCV001096623	SCV001252846	likely benign	Encephalopathy due to GLUT1 deficiency	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001098347	SCV001254707	likely benign	Dystonia 9	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000189348	SCV002009551	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000189348	SCV004563616	uncertain significance	not provided	2023-11-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700575	SCV005202786	uncertain significance	not specified	2024-07-26	criteria provided, single submitter	clinical testing	Variant summary: SLC2A1 c.125A>C (p.Glu42Ala) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250562 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.125A>C in individuals affected with GLUT1 Deficiency Syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 207186). Based on the evidence outlined above, the variant was classified as uncertain significance.