Submissions for variant NM_006516.4(SLC2A1):c.274C>A (p.Arg92=)

dbSNP: rs202060209

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000400449	SCV000357709	benign	Dystonia 9	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000722005	SCV000357710	benign	Encephalopathy due to GLUT1 deficiency	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Eurofins Ntd Llc (ga)	RCV000732647	SCV000860623	uncertain significance	not provided	2018-04-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001364077	SCV001560209	uncertain significance	GLUT1 deficiency syndrome 1, autosomal recessive	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change affects codon 92 of the SLC2A1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SLC2A1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs202060209, gnomAD 0.02%). 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: 207181). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298514	SCV002598842	uncertain significance	not specified	2022-09-30	criteria provided, single submitter	clinical testing	Variant summary: SLC2A1 c.274C>A (p.Arg92Arg) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 250800 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge c.274C>A has not been reported in the literature in individuals affected with GLUT1 Deficiency Syndrome 1 and no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
SingHealth Duke-NUS Institute of Precision Medicine	RCV000722005	SCV000853174	uncertain significance	Encephalopathy due to GLUT1 deficiency	2017-06-07	no assertion criteria provided	curation