Submissions for variant NM_000151.4(G6PC1):c.884G>A (p.Arg295His)

gnomAD frequency: 0.00001  dbSNP: rs375212414

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002237510	SCV002510559	likely pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2024-05-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 295 of the G6PC protein (p.Arg295His). This variant is present in population databases (rs375212414, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with G6PC-related conditions. ClinVar contains an entry for this variant (Variation ID: 1682529). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg295 amino acid residue in G6PC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8211187, 10070617, 12373566, 18083610). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	RCV002237510	SCV005076328	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2024-04-12	criteria provided, single submitter	clinical testing	Variant summary: G6PC1 c.884G>A (p.Arg295His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251420 control chromosomes (gnomAD). c.884G>A has been reported in the literature in an individual affected with Glycogen Storage Disease Type Ia who was reported as compound heterozygous with a pathogenic variant (Haring_2022). At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in <10% of normal phosphohydrolase activity (Lei_1995). Another missense variant affecting this amino acid has been classified as pathogenic, suggesting this is a functionally important residue. The following publications have been ascertained in the context of this evaluation (PMID: 35811762, 7744838). ClinVar contains an entry for this variant (Variation ID: 1682529). Based on the evidence outlined above, the variant was classified as pathogenic.