Submissions for variant NM_000151.4(G6PC1):c.562G>C (p.Gly188Arg)

gnomAD frequency: 0.00003  dbSNP: rs80356482

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012788	SCV000695639	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2017-06-22	criteria provided, single submitter	clinical testing	Variant summary: The G6PC c.562G>C (p.Gly188Arg) variant involves the alteration of a conserved nucleotide located in a transmembrane helix, which are critical for the correct folding, stability, and enzymatic activity of G6Pase (Shieh_2002). 4/4 in silico tools predict a damaging outcome, in addition, the variant is located in the last 3' nucleotide position in exon 4, which 4/5 splice prediction tools predict an impact on splicing. A functional study, Shieh_2002, indicates the variant greatly reduced G6Pase activity. This variant was found in 8/121410 control chromosomes at a frequency of 0.0000659, which does not exceed the estimated maximal expected allele frequency of a pathogenic G6PC variant (0.0017321). Multiple publications have cited the variant in affected compound heterozygote and homozygote individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000012788	SCV000961394	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2023-10-13	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 188 of the G6PC protein (p.Gly188Arg). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is present in population databases (rs80356482, gnomAD 0.01%). This missense change has been observed in individuals with glycogen storage disease type Ia (PMID: 8733042, 10960498). ClinVar contains an entry for this variant (Variation ID: 12008). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects G6PC function (PMID: 10612834, 10960498, 11739393). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Gly188 amino acid residue in G6PC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7573034, 24565827). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000012788	SCV001163787	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000012788	SCV001193873	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2019-12-20	criteria provided, single submitter	clinical testing	NM_000151.3(G6PC):c.562G>C(G188R) is classified as pathogenic in the context of glycogen storage disease type Ia. Please note homozygosity for G188R has been reported to be associated with a GSD type Ib-like phenotype with neutropenia.. Sources cited for classification include the following: PMID 23352793, 11058903, 11739393, 8733042, 10612834, 10874313, 12373566 and 10960498. Classification of NM_000151.3(G6PC):c.562G>C(G188R) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.‚Äã
Revvity Omics, Revvity	RCV000012788	SCV002023774	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2022-12-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000012788	SCV002793268	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2022-03-08	criteria provided, single submitter	clinical testing
GeneDx	RCV001723560	SCV004031796	pathogenic	not provided	2023-08-27	criteria provided, single submitter	clinical testing	Published functional studies demonstrate G188R is associated with significantly reduced G6Pase enzyme activity compared to controls (Shieh et al., 2002; Weston et al., 2000); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29365308, 31589614, 11739393, 7573034, 10874313, 10960498, 12373566, 34308104, 32191290, 8733042, 11058903, 10612834)
Mayo Clinic Laboratories, Mayo Clinic	RCV001723560	SCV004228177	pathogenic	not provided	2022-06-21	criteria provided, single submitter	clinical testing	PP3, PM2, PM3, PS3, PS4
OMIM	RCV000012788	SCV000033028	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2000-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000012788	SCV000040460	not provided	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA		no assertion provided	literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723560	SCV001958521	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723560	SCV001969595	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000012788	SCV002093314	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2017-03-17	no assertion criteria provided	clinical testing