ClinVar Miner

Submissions for variant NM_000151.4(G6PC1):c.509G>A (p.Arg170Gln)

gnomAD frequency: 0.00002  dbSNP: rs750470654
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194214 SCV001363565 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2019-05-31 criteria provided, single submitter clinical testing Variant summary: G6PC c.509G>A (p.Arg170Gln) results in a conservative amino acid change located in the Phosphatidic acid phosphatase type 2/haloperoxidase (IPR000326) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251466 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals (both homozygous and compound heterozygous) affected with Glycogen Storage Disease Type Ia (Barkaoui_2007, Huner_1998, Matern_2002). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant completely abolished phosphohydrolase activity; this incidcating the importance of this residue in G6Pase catalysis (Shieh_2002). No submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001194214 SCV001401714 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2023-12-21 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 170 of the G6PC protein (p.Arg170Gln). This variant is present in population databases (rs750470654, gnomAD 0.002%). This missense change has been observed in individual(s) with glycogen storage disease (PMID: 9700612, 10834516). ClinVar contains an entry for this variant (Variation ID: 929150). 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 80%. Experimental studies have shown that this missense change affects G6PC function (PMID: 11739393). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV001194214 SCV002809812 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2021-09-12 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV001194214 SCV003820065 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2022-05-18 criteria provided, single submitter clinical testing
Natera, Inc. RCV001194214 SCV002093310 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2017-03-17 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV003396803 SCV004120681 pathogenic G6PC1-related disorder 2024-05-20 no assertion criteria provided clinical testing The G6PC1 c.509G>A variant is predicted to result in the amino acid substitution p.Arg170Gln. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with glycogen storage disease type Ia (Hüner et al. 1998. PubMed ID: 9700612; Rake et al. 2000. PubMed ID: 10834516; Barkaoui et al. 2007. PubMed ID: 18008183; Muzetti et al. 2021. PubMed ID: 34093448). Additionally, an in vitro experimental study found that the presence of this variant leads to a total loss of enzymatic activity compared to wild type G6PC1 (Shieh et al. 2002. PubMed ID: 11739393). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

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