chr17-42903947-C-T
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 15P and 1B. PM1PM2PM5PP3PP5_Very_StrongBP4
The NM_000151.4(G6PC1):c.247C>T(p.Arg83Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,611,788 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R83I) has been classified as Likely pathogenic.
Frequency
Genomes: 𝑓 0.00035 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00040 ( 1 hom. )
Consequence
G6PC1
NM_000151.4 missense
NM_000151.4 missense
Scores
15
2
2
Clinical Significance
Conservation
PhyloP100: 2.67
Genes affected
G6PC1 (HGNC:4056): (glucose-6-phosphatase catalytic subunit 1) Glucose-6-phosphatase (G6Pase) is a multi-subunit integral membrane protein of the endoplasmic reticulum that is composed of a catalytic subunit and transporters for G6P, inorganic phosphate, and glucose. This gene (G6PC) is one of the three glucose-6-phosphatase catalytic-subunit-encoding genes in human: G6PC, G6PC2 and G6PC3. Glucose-6-phosphatase catalyzes the hydrolysis of D-glucose 6-phosphate to D-glucose and orthophosphate and is a key enzyme in glucose homeostasis, functioning in gluconeogenesis and glycogenolysis. Mutations in this gene cause glycogen storage disease type I (GSD1). This disease, also known as von Gierke disease, is a metabolic disorder characterized by severe hypoglycemia associated with the accumulation of glycogen and fat in the liver and kidneys.[provided by RefSeq, Feb 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
In a binding_site (size 0) in uniprot entity G6PC1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000151.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]
PP5
Variant 17-42903947-C-T is Pathogenic according to our data. Variant chr17-42903947-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-42903947-C-T is described in Lovd as [Pathogenic]. Variant chr17-42903947-C-T is described in Lovd as [Likely_pathogenic]. Variant chr17-42903947-C-T is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.28041). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| G6PC1 | ENST00000253801.7 | c.247C>T | p.Arg83Cys | missense_variant | Exon 2 of 5 | 1 | NM_000151.4 | ENSP00000253801.1 | ||
| G6PC1 | ENST00000592383.5 | c.247C>T | p.Arg83Cys | missense_variant | Exon 2 of 5 | 2 | ENSP00000465958.1 | |||
| G6PC1 | ENST00000585489.1 | c.247C>T | p.Arg83Cys | missense_variant | Exon 2 of 4 | 5 | ENSP00000466202.1 | |||
| G6PC1 | ENST00000588481.1 | n.312C>T | non_coding_transcript_exon_variant | Exon 2 of 2 | 2 |
Frequencies
GnomAD3 genomes 0.000348 AC: 53AN: 152126Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000573 AC: 144AN: 251452Hom.: 1 AF XY: 0.000508 AC XY: 69AN XY: 135900
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GnomAD4 exome AF: 0.000400 AC: 584AN: 1459662Hom.: 1 Cov.: 30 AF XY: 0.000409 AC XY: 297AN XY: 726290
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GnomAD4 genome 0.000348 AC: 53AN: 152126Hom.: 0 Cov.: 31 AF XY: 0.000269 AC XY: 20AN XY: 74314
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:28Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Pathogenic:20Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 18, 2019 | 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. - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 30, 2004 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 02, 2025 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Pathology and Clinical Laboratory Medicine, King Fahad Medical City | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 13, 2016 | 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. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Oct 11, 2020 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 01, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Dec 15, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Mar 05, 2018 | - - |
| Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Breakthrough Genomics, Breakthrough Genomics | Dec 08, 2021 | 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]. - |
| Pathogenic, criteria provided, single submitter | research | Kids Research, The Children's Hospital at Westmead | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 15, 2024 | The G6PC1 c.247C>T; p.Arg83Cys variant (rs1801175, ClinVar Variation ID: 11998), also known as C326T in the literature, is reported in multiple unrelated individuals with glycogen storage disease who are homozygous or compound heterozygous with another G6PC1 variant (Carves 2003, Chan 2018, Hannah 2022, Lei 1993, Trioche 1998, Qu 1996). This variant is observed in the general population with an overall allele frequency of 0.05% (151/282828 alleles, including 1 homozygote) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.829). In support of these predictions, functional analyses have shown the variant protein levels are significantly reduced compared to wild type and the variant protein shows abnormal localization (Plona 2021). Based on available information, this variant is considered to be pathogenic. References: Carves C et al. Gouty tendinitis revealing glycogen storage disease Type Ia in two adolescents. Joint Bone Spine. 2003 Mar;70(2):149-53. PMID: 12713862. Chan YM et al. Case 3-2018: A 5-Month-Old Boy with Hypoglycemia. N Engl J Med. 2018 Jan 25;378(4):381-389. PMID: 29365308. Hannah WB et al. Very early-onset inflammatory bowel disease: Novel description in glycogen storage disease type Ia. Mol Genet Metab Rep. 2022 Feb 15;31:100848. PMID: 35242580. Lei KJ et al. Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a. Science. 1993 Oct 22;262(5133):580-3. PMID: 8211187. Plona KL et al. Classifying molecular phenotypes of G6PC variants for pathogenic properties and to guide therapeutic development. JIMD Rep. 2021 Mar 28;60(1):56-66. PMID: 34258141. Trioche P et al. Prenatal diagnosis of glycogen storage disease type Ia by restriction enzyme digestion. Prenat Diagn. 1998 Jun;18(6):629-31. PMID: 9664612. Qu Y et al. Molecular prenatal diagnosis of glycogen storage disease type Ia. Prenat Diagn. 1996 Apr;16(4):333-6. PMID: 8734807. - |
| Pathogenic, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion, Medical Genetics | Sep 01, 2022 | 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. - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 20, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 20, 2022 | 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) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 27, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | G6PC1: PM3:Very Strong, PM1, PM5, PP4:Moderate, PS3:Moderate, PM2:Supporting, PP3 - |
not specified Pathogenic:2
| Pathogenic, criteria provided, single submitter | research | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Mar 17, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 03, 2022 | 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. - |
Glycogen storage disease Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 06, 2016 | 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. - |
Hypoglycemia;C0349588:Short stature Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;D;.
REVEL
Pathogenic
Sift
Pathogenic
.;D;.
Sift4G
Pathogenic
D;D;D
Polyphen
1.0
.;D;.
Vest4
MVP
MPC
0.93
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at