Submissions for variant NM_000151.4(G6PC1):c.247C>T (p.Arg83Cys)

gnomAD frequency: 0.00034  dbSNP: rs1801175

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000012778	SCV000223927	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2014-12-15	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000424594	SCV000227025	pathogenic	not provided	2018-06-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000012778	SCV000402976	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2017-04-27	criteria provided, single submitter	clinical testing	The G6PC c.247C>T (p.Arg83Cys) variant is widely reported in the literature as a pathogenic variant for glycogen storage disease type I. The variant has been described in several studies as the most prevalent variant for this disease in the Ashkenazi Jewish population (Ekstein et al. 2004; Bali et al. 2006; Froissart et al. 2011). Across eight studies of individuals of different ethnic origins with glycogen storage disease type I, the p.Arg83Cys variant was reported in 35% (110/312) of alleles including at least 25 individuals in whom the variant was found in a homozygous state and seven in whom the variant was found in a compound heterozygous state (Lei et al. 1993; Lei et al. 1994; Lei et al. 1995; Parvari et al. 1997; Rake et al. 2000; Seydewitz et al. 2000; Sever et al. 2012; Carlin et al. 2013). All individuals showed significantly reduced or undetectable enzyme activity in liver biopsy samples. No control data were available from these studies, though the variant is reported at a frequency of 0.00090 in the European (non-Finnish) population of the Exome Aggregation Consortium. Transient expression studies of the variant by Lei et al. (1993) demonstrated that the p.Arg83Cys abolishes enzyme activity. Based on the collective evidence, the p.Arg83Cys variant is classified as pathogenic for glycogen storage disease type I. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000424594	SCV000520992	pathogenic	not provided	2022-01-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate loss of glucose-6-phosphatase enzyme activity (Shieh et al., 2002; Chou et al., 2008); 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: 12713862, 23312056, 8734807, 25333069, 24082139, 8211187, 18449899, 7623438, 15316959, 11739393, 28360385, 28397058, 29365308, 9664612, 30609409, 30202406, 31980526, 32313153, 33224545, 34426522, 34093448, 34258141, 31589614, 33763395, 33101979, 33258288, 31319225)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000012778	SCV000658103	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 83 of the G6PC protein (p.Arg83Cys). This variant is present in population databases (rs1801175, gnomAD 0.7%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with glycogen storage disease (PMID: 7623438, 10834516, 15316959, 18008183, 23312056, 24385852). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.326C>T. ClinVar contains an entry for this variant (Variation ID: 11998). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt G6PC protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects G6PC function (PMID: 7744838). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012778	SCV000695636	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2016-05-13	criteria provided, single submitter	clinical testing	Variant summary: The G6PC c.247C>T (p.Arg83Cys) variant involves the alteration of a conserved nucleotide resulting in a replacement of and Arginine with a Cystein located in the conserved phosphatase signature motif of G6PC. Mutations of the phosphatase active site residues are known to be clinically relevant; they predispose individuals to Glycogen Storage Disease (Clinvar, HGMD). Consistently, 5/5 in silico tools predict this variant to be deleterious. The variant was found in 64/121294 control chromosomes (1 homozygote) at a frequency of 0.0005276, which does not exceed the estimated maximal expected allele frequency of a pathogenic G6PC variant (0.0017321). It was reported in several GSD patients in either homozygosity or in compound heterozygosity with other pathogenic variant indicating a disease causing impact. A functional study demonstrated the variant to result in complete inactivation of the enzyme, confirming the importance of an intact Arg83 residue in G6Pase catalysis and further supporting pathogenicity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as Pathogenic. Taken together, this variant is classified as a Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000360229	SCV000712202	pathogenic	Glycogen storage disease	2016-06-06	criteria provided, single submitter	clinical testing	The p.Arg83Cys variant in G6PC is the most frequent pathogenic variant implicate d in Glycogen storage disease type I in the Ashkenazi Jewish population (Parvari 1997, Lei 1995, Ekstein 2004). This variant has also been identified 0.09% (60/ 66,646) of European chromosomes by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org; dbSNP rs1801175). In vitro functional studies also p rovide evidence that the p.Arg83Cys variant may impact protein function (Lei 199 3). In summary, this variant meets our criteria to be classified as pathogenic f or Glycogen storage disease type I in an autosomal recessive manner based upon i ts identification in patients and functional impact.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626623	SCV000747324	pathogenic	Short stature; Hypoglycemia	2017-01-01	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000012778	SCV000784537	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2018-03-05	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000424594	SCV000801484	pathogenic	not provided	2024-06-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000012778	SCV000894121	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2018-10-31	criteria provided, single submitter	clinical testing
Pathology and Clinical Laboratory Medicine, King Fahad Medical City	RCV000012778	SCV000996289	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA		criteria provided, single submitter	clinical testing
Mendelics	RCV000012778	SCV001140451	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2019-05-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000012778	SCV001163780	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000012778	SCV001194060	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2019-10-18	criteria provided, single submitter	clinical testing	NM_000151.3(G6PC):c.247C>T(R83C) is classified as pathogenic in the context of glycogen storage disease type Ia. Sources cited for classification include the following: PMID: 10874313, 12093795, 8734807, 7814621, 15316959, 24082139, 12373566, and 9332655. Classification of NM_000151.3(G6PC):c.247C>T(R83C) 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.
Kids Research, The Children's Hospital at Westmead	RCV000012778	SCV001244747	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA		criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000424594	SCV001246604	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	G6PC1: PM3:Very Strong, PM1, PM5, PP4:Moderate, PS3:Moderate, PM2:Supporting, PP3
Revvity Omics, Revvity	RCV000012778	SCV002023776	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2023-01-01	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000012778	SCV002573306	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.053%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.83; 3Cnet: 0.97). It has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011998). A different missense change at the same codon (p.Arg83His) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000038300). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV003987317	SCV003549547	pathogenic	not specified	2022-06-03	criteria provided, single submitter	clinical testing	The c.247C>T (p.R83C) alteration is located in exon 2 (coding exon 2) of the G6PC gene. This alteration results from a C to T substitution at nucleotide position 247, causing the arginine (R) at amino acid position 83 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.05% (151/282828) total alleles studied. The highest observed frequency was 0.66% (68/10370) of Ashkenazi Jewish alleles. This alteration has been detected in the homozygous state, and in conjunction with other pathogenic mutations in G6PC1, in multiple individuals with G6PC1-related glycogen storage disease type I (Peeks, 2017; Lei, 1994; Düzenli, 2019; Lei, 1993; Saneifard, 2020; Riley, 2020; Muzetti, 2021; Fang, 2021). It has also been found to segregate in affected individuals in the same family (Carvès, 2003). Another alteration at the same codon, p.R83H (c.248G>A), has been described in individuals with G6PC1-related glycogen storage disease type I (Lei, 1995; Fang, 2021). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003987317	SCV004805179	pathogenic	not specified	2024-03-17	criteria provided, single submitter	research
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000012778	SCV005051772	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2024-02-01	criteria provided, single submitter	curation
Breakthrough Genomics, Breakthrough Genomics	RCV000012778	SCV005088759	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2021-12-08	criteria provided, single submitter	clinical testing	This variant was previously reported in patients with glycogen storage disease in homozygous or compound heterozygous state and reported to segregate with glycogen storage disease type 1a in a family [PMID: 8211187, 23312056, 18008183, 15316959, 15316959, 7623438, 24385852, 10834516]. Functional studies suggested that this variant reduces enzyme activity [PMID: 7744838, 11739393, 18449899].
OMIM	RCV000012778	SCV000033018	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2004-08-30	no assertion criteria provided	literature only
GeneReviews	RCV000012778	SCV000040456	not provided	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA		no assertion provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000012778	SCV001142473	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2020-01-06	no assertion criteria provided	curation	NM_000151.3:c.247C>T is also known as c.326C>T in the literature. NM_000151.3:c.247C>T in the G6PC gene has an allele frequency of 0.007 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant has been reported to segregate with glycogen storage disease type 1a in a single family (PMID: 8211187) and has been reported as homozygous or in combination with another G6PC variant in individuals affected with glycogen storage disease type 1A (PMID: 23312056). Ekstein et al reported 30 Glycogen storage disease type Ia patient in Ashkenazi Jewish origin. All of them are homozygous of this variant (PMID: 15316959). Experimental studies have shown that this missense change severely reduces enzyme activity of the protein encoded by G6PC (PMID: 7744838). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PM3_Strong; PP4; PP1.
Natera, Inc.	RCV000012778	SCV001463398	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2020-09-16	no assertion criteria provided	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000012778	SCV001469244	likely pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2020-10-11	no assertion criteria provided	clinical testing