Submissions for variant NM_000340.2(SLC2A2):c.1093C>T (p.Arg365Ter)

gnomAD frequency: 0.00002  dbSNP: rs121909742

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000017472	SCV001414737	pathogenic	Fanconi-Bickel syndrome	2019-10-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SLC2A2 are known to be pathogenic (PMID: 11810292). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individuals and families affected with Fanconi-Bickel syndrome (PMID: 9354798, 11810292). ClinVar contains an entry for this variant (Variation ID: 16092). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg365*) in the SLC2A2 gene. It is expected to result in an absent or disrupted protein product.
Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi	RCV000017472	SCV002102792	pathogenic	Fanconi-Bickel syndrome	2022-03-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490379	SCV002794729	pathogenic	Type 2 diabetes mellitus; Fanconi-Bickel syndrome	2022-03-22	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV000017472	SCV003929436	pathogenic	Fanconi-Bickel syndrome		criteria provided, single submitter	clinical testing	A Heterozygous Nonsense variant c.1093C>T in Exon 9 of the SLC2A2 gene that results in the amino acid substitution p.Arg365* was identified. The observed variant has a maximum allele frequency of 0.00001/0.00006% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. This variant has been reported as Pathogenic in the ClinVar database (Variant ID: 16092). This variant was reported among patients for Fanconi-Bickel syndrome (Santer R et al., 2002). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
GeneDx	RCV004719651	SCV005324965	pathogenic	not provided	2023-11-27	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 9354798, 27617158, 24175243, 11810292, 21972075, 17994282, 35738466, 36140215)
OMIM	RCV000017472	SCV000037744	pathogenic	Fanconi-Bickel syndrome	2002-01-01	no assertion criteria provided	literature only
Genetics and Genomics Program, Sidra Medicine	RCV004732549	SCV005367931	pathogenic	Congenital long QT syndrome		no assertion criteria provided	research	The c.1093C>T stop gained variant in SLC2A2 is reported in ClinVar as pathogenic (SCV000535871) and is absent in homozygous form in population databases like gnomAD, with a frequency of 0.0000637 (PM2). This variant results in a premature stop codon, likely causing loss of function (PVS1). The variant is classified as pathogenic (ACMG codes: PVS1, PM2, PP3, PP5).