Submissions for variant NM_000151.4(G6PC1):c.562G>A (p.Gly188Ser)

dbSNP: rs80356482

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197003	SCV000251527	pathogenic	not provided	2016-10-17	criteria provided, single submitter	clinical testing	The G188S missense pathogenic variant in the G6PC gene has been reported previously in association with glycogen storage disease type 1a (Lei et al., 1995). Expression studies found that the G188S mutation abolishes G6Pase activity (Lei et al., 1995). Furthermore, G188S is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and another missense mutation at the same position (G188R) has also been reported in association with glycogen storage disease type 1a. Therefore, we interpret G188S to be a pathogenic variant. The variant is found in MITONUC-MITOP panel(s).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587142	SCV000695638	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2016-04-04	criteria provided, single submitter	clinical testing	Variant Summary: The variant of interest causes a missense change involving a conserved nucleotide 5/5 in silico programs predicting a "deleterious" outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121410, which does not exceed the predicted maximum expected allele frequency for a pathogenic G6PC variant of 1/577. The variant of interest has been reported in affected individuals via publications, along with a reputable clinical laboratory citing the variant as "pathogenic." In addition, multiple functional studies indicate the variant to inactivate G6Pase enzyme activity. Furthermore, another variant at this position, c.562G>C (p.Gly188Arg) has been reported as pathogenic. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
Invitae	RCV000587142	SCV000776252	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 188 of the G6PC protein (p.Gly188Ser). 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 0.004%). This missense change has been observed in individuals with glycogen storage disease type 1A (PMID: 7573034, 24565827; Invitae). This variant is also known as c.641G>A or G641A. ClinVar contains an entry for this variant (Variation ID: 214465). 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: 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: 8733042, 10834516, 10960498, 11739393). 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	RCV000587142	SCV001163786	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA		criteria provided, single submitter	clinical testing
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000587142	SCV001251515	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA		criteria provided, single submitter	research	The c.562G>A (p.G188S) missense variant has been reported in individuals with glycogen storage disease type Ia (PMID: 7573034; 12373566; 24565827).
Genetics and Molecular Pathology, SA Pathology	RCV000587142	SCV002556438	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2021-07-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000587142	SCV002810635	likely pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2022-04-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000587142	SCV003833776	likely pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2022-06-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000197003	SCV004009791	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	G6PC1: PM2, PM5, PP4:Moderate, PS3:Moderate, PM3:Supporting, PP3
Counsyl	RCV000587142	SCV000791230	likely pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2017-05-14	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000587142	SCV002093313	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2017-03-17	no assertion criteria provided	clinical testing