Submissions for variant NM_006516.4(SLC2A1):c.653G>A (p.Arg218His)

gnomAD frequency: 0.00004  dbSNP: rs374080633

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657887	SCV000779650	likely benign	not provided	2019-02-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20630673, 29199027, 20129935, 17718830, 18387950, 23340081, 16217704, 31196579)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079315	SCV001009972	likely pathogenic	GLUT1 deficiency syndrome 1, autosomal recessive	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 218 of the SLC2A1 protein (p.Arg218His). This variant is present in population databases (rs374080633, gnomAD 0.1%). This missense change has been observed in individual(s) with autosomal recessive GLUT1 deficiency (PMID: 31196579). This variant has been reported in individual(s) with clinical features of autosomal dominant GLUT1 deficiency (PMID: 23340081, 16217704, 26193382); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 546093). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC2A1 function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Illumina Laboratory Services, Illumina	RCV001098262	SCV001254616	benign	Dystonia 9	2018-01-16	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001098263	SCV001254617	benign	Encephalopathy due to GLUT1 deficiency	2018-01-16	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Ambry Genetics	RCV001266484	SCV001444659	uncertain significance	Inborn genetic diseases	2021-08-06	criteria provided, single submitter	clinical testing	The c.653G>A (p.R218H) alteration is located in exon 5 (coding exon 5) of the SLC2A1 gene. This alteration results from a G to A substitution at nucleotide position 653, causing the arginine (R) at amino acid position 218 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (20/282802) total alleles studied. The highest observed frequency was 0.11% (11/10368) of Ashkenazi Jewish alleles. this variant was detected in two individuals suspected to have GLUT1 deficiency (Klepper, 2005; Leen, 2010). It was also identified alone in 7 asymptomatic individuals in one family; four symptomatic relatives with a range of symptoms were heterozygous for both p.R218H and p.R458W (Tzadok, 2014). In addition, p.R218H was reported in cis with p.A197P, with a splice site variant on the opposite allele in an individual with hypotonia and abnormal ocular movements; the phase was confirmed via testing of the asymptomatic parents (Hully, 2015). This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004737938	SCV005347775	uncertain significance	SLC2A1-related disorder	2024-08-27	no assertion criteria provided	clinical testing	The SLC2A1 c.653G>A variant is predicted to result in the amino acid substitution p.Arg218His. This variant has been reported in a heterozygous state in individuals with suspected Glucose transporter type 1 (GLUT1) deficiency syndrome (Klepper et al.2005. PubMed ID: 16217704; Leen et al. 2010. PubMed ID: 20129935; Heussinger et al. 2018. PubMed ID: 29199027); however, the role of the variant in this condition is currently unclear as reported phenotypes were limited. This variant has been noted as paternally-inherited in the compound heterozygous state in a patient with reported autosomal recessive GLUT1 deficiency (Dozières-Puyravel et al. 2019. PubMed ID: 31196579). This variant has been reported in a cis (on the opposite allele) with a pathogenic variant (c.1372C>T; p.Arg458Trp) in four symptomatic family members with GLUT1 deficiency, but was observed alone (heterozygous) in seven unaffected family members (Tzadok et al. 2013. PubMed ID: 23340081). This variant was noted in the compound heterozygous state with c.589G>C (p.Ala197Pro) in an individual with hypotonia and abnormal ocular movements; phase was confirmed via testing of the asymptomatic parents (Hully et al. 2015. PubMed ID: 26193382). The variant is reported in 0.11% of alleles in individuals of Ashkenazi Jewish descent, 0.016% in Finnish Europeans, and 0.0031% in non-Finnish Europeans in gnomAD. This variant has conflicting classifications listed in ClinVar ranging from benign to likely pathogenic (https://preview.ncbi.nlm.nih.gov/clinvar/variation/546093/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.