Submissions for variant NM_006516.4(SLC2A1):c.668G>A (p.Arg223Gln)

gnomAD frequency: 0.00002  dbSNP: rs397514564

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001045125	SCV001208959	uncertain significance	GLUT1 deficiency syndrome 1, autosomal recessive	2024-12-02	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 223 of the SLC2A1 protein (p.Arg223Gln). This variant is present in population databases (rs397514564, gnomAD 0.006%). This missense change has been observed in individual(s) with idiopathic generalized epilepsy (PMID: 23280796, 35571021). ClinVar contains an entry for this variant (Variation ID: 842670). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SLC2A1 protein function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SLC2A1 function (PMID: 23280796, 25982116). This variant disrupts the p.Arg223 amino acid residue in SLC2A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25564316, 26537434). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Illumina Laboratory Services, Illumina	RCV001098259	SCV001254613	uncertain significance	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV001546081	SCV001765535	uncertain significance	not provided	2019-12-13	criteria provided, single submitter	clinical testing	Reported previously in an individual with idiopathic generalized epilepsy (Arsov et al., 2012); Published functional studies suggest that the R223Q variant may impact protein function (Lee et al., 2015); This variant is associated with the following publications: (PMID: 28717674, 23280796, 25982116)
Ambry Genetics	RCV002363593	SCV002663541	uncertain significance	Inborn genetic diseases	2018-03-14	criteria provided, single submitter	clinical testing	The p.R223Q variant (also known as c.668G>A), located in coding exon 5 of the SLC2A1 gene, results from a G to A substitution at nucleotide position 668. The arginine at codon 223 is replaced by glutamine, an amino acid with highly similar properties. This variant did not co-segregate with disease in one individual tested in our laboratory. This alteration was identified in an individual with idiopathic generalized epilepsy, however functional analysis did not show a significant impact on transport (Arsov T et al. Ann. Neurol., 2012 Nov;72:807-15). Subsequent functional studies however demonstrated a negative functional impact for three variants at this position, including R223Q, R223P, and R223W (Lee EE et al. Mol. Cell, 2015 Jun;58:845-53). This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Neuberg Centre For Genomic Medicine, NCGM	RCV003389331	SCV004101515	uncertain significance	Encephalopathy due to GLUT1 deficiency		criteria provided, single submitter	clinical testing	The missense variant p.R223Q in SLC2A1 (NM_006516.4) has been previously reported in an individual affected with idiopathic generalized epilepsy (Arsov et al, 2012). This variant has been reported to have conflicting or insufficient data to determine the effect on SLC2A1 protein function (Lee et al, 2015). The p.Arg223Gln variant has a GnomAD frequency of 0.001193 % and is novel (not in any individuals) in 1000 Genomes. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Arg223Gln in SLC2A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. The observed variant was also detected in the spouse.
Genome-Nilou Lab	RCV003446595	SCV004173342	uncertain significance	Epilepsy, idiopathic generalized, susceptibility to, 12	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001098259	SCV004173343	uncertain significance	Dystonia 9	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003389331	SCV004173344	uncertain significance	Encephalopathy due to GLUT1 deficiency	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003446594	SCV004173346	uncertain significance	Childhood onset GLUT1 deficiency syndrome 2	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003446596	SCV004173347	uncertain significance	Hereditary cryohydrocytosis with reduced stomatin	2023-04-11	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001546081	SCV005411841	uncertain significance	not provided	2024-09-19	criteria provided, single submitter	clinical testing