Submissions for variant NM_000340.2(SLC2A2):c.158G>A (p.Arg53Gln) (rs145210664)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000490046	SCV000577580	uncertain significance	not provided	2018-04-16	criteria provided, single submitter	clinical testing	The R53Q variant in the SLC2A2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R53Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R53Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R53Q as a variant of uncertain significance.
Fulgent Genetics,Fulgent Genetics	RCV000764477	SCV000895548	uncertain significance	Type 2 diabetes mellitus; Fanconi-Bickel syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV001147021	SCV001307788	uncertain significance	Fanconi-Bickel syndrome	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV001147021	SCV001400651	uncertain significance	Fanconi-Bickel syndrome	2019-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 53 of the SLC2A2 protein (p.Arg53Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs145210664, ExAC 0.09%). This variant has not been reported in the literature in individuals with SLC2A2-related disease. ClinVar contains an entry for this variant (Variation ID: 426982). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.