Submissions for variant NM_006516.4(SLC2A1):c.1034C>T (p.Ala345Val)

gnomAD frequency: 0.00004  dbSNP: rs769943554

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000192772	SCV000248911	likely benign	not specified	2016-04-20	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000725496	SCV000337327	uncertain significance	not provided	2018-03-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000316012	SCV000357679	benign	Dystonia 9	2018-01-13	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	RCV000372948	SCV000357680	benign	Encephalopathy due to GLUT1 deficiency	2018-01-13	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.
GeneDx	RCV000725496	SCV000515640	likely benign	not provided	2020-10-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000648088	SCV000769898	uncertain significance	GLUT1 deficiency syndrome 1, autosomal recessive	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 345 of the SLC2A1 protein (p.Ala345Val). This variant is present in population databases (rs769943554, gnomAD 0.04%). 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: 212202). 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 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.
Ambry Genetics	RCV002390506	SCV002699698	likely benign	Inborn genetic diseases	2017-09-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000192772	SCV004122763	likely benign	not specified	2023-10-11	criteria provided, single submitter	clinical testing	Variant summary: SLC2A1 c.1034C>T (p.Ala345Val) results in a non-conservative amino acid change in 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 8.8e-05 in 250870 control chromosomes (i.e. in 22 carriers). The relatively high occurrence of heterozygous control individuals suggests that the variant is likely not associated with a high penetrance, early onset dominant disease phenotype. To our knowledge, no occurrence of c.1034C>T in individuals affected with GLUT1 Deficiency Syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign.