Submissions for variant NM_000151.4(G6PC1):c.202G>A (p.Gly68Arg)

dbSNP: rs1567702819

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002237083	SCV002510569	likely pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2022-08-19	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 68 of the G6PC protein (p.Gly68Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with glycogen storage disease (PMID: 9700613, 11310582, 33258288). ClinVar contains an entry for this variant (Variation ID: 1682484). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt G6PC protein function. Experimental studies have shown that this missense change affects G6PC function (PMID: 11739393). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002237083	SCV004100199	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2023-09-01	criteria provided, single submitter	clinical testing	Variant summary: G6PC1 c.202G>A (p.Gly68Arg) results in a non-conservative amino acid change located in the phosphatidic acid phosphatase type 2/haloperoxidase domain (IPR000326) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251406 control chromosomes (gnomAD). c.202G>A has been reported in the literature as a biallelic genotype in individuals affected with Glycogen Storage Disease Type Ia, most of whom were of Brazilian ancestry (e.g. Sartorato_1998, Reis_2001, Matern_2002, Sperb-Ludwig_2019, Quaio_2020). These data indicate that the variant is likely to be associated with disease. A functional study evaluating an impact of the variant in vitro found that it had <10% enzymatic activity compared to the WT (Shieh_2002). The following publications have been ascertained in the context of this evaluation (PMID: 12373566, 33258288, 11310582, 9700613, 31508908, 11739393). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.