NM_000151.4(G6PC1):c.247C>T (p.Arg83Cys) AND Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
- Germline classification:
- Pathogenic (22 submissions)
- Last evaluated:
- Jan 24, 2026
- Review status:
- 2 stars out of maximum of 4 starscriteria provided, multiple submitters, no conflicts
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000012778.56
Allele description [Variation Report for NM_000151.4(G6PC1):c.247C>T (p.Arg83Cys)]
NM_000151.4(G6PC1):c.247C>T (p.Arg83Cys)
- Gene:
- G6PC1:glucose-6-phosphatase catalytic subunit 1 [Gene - OMIM - HGNC]
- Variant type:
- single nucleotide variant
- Cytogenetic location:
- 17q21.31
- Genomic location:
- Preferred name:
- NM_000151.4(G6PC1):c.247C>T (p.Arg83Cys)
- Other names:
- G6PC, ARG83CYS
- HGVS:
- NC_000017.11:g.42903947C>T
- NG_011808.1:g.8150C>T
- NM_000151.4:c.247C>TMANE SELECT
- NM_001270397.2:c.247C>T
- NP_000142.2:p.Arg83Cys
- NP_001257326.1:p.Arg83Cys
- LRG_147t1:c.247C>T
- LRG_147:g.8150C>T
- LRG_147p1:p.Arg83Cys
- NC_000017.10:g.41055964C>T
- NM_000151.2:c.247C>T
- NM_000151.3:c.247C>T
- NM_001270397.1:c.247C>T
- NP_000142.1:p.Arg83Cys
- P35575:p.Arg83Cys
This HGVS expression did not pass validation- Protein change:
- R83C; ARG83CYS
- Links:
- UniProtKB: P35575#VAR_005239; OMIM: 613742.0002; dbSNP: rs1801175
- Molecular consequence:
- NM_000151.4:c.247C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001270397.2:c.247C>T - missense variant - [Sequence Ontology: SO:0001583]
- Observations:
- 9
Condition(s)
- Name:
- Glycogen storage disease due to glucose-6-phosphatase deficiency type IA (GSD1A)
- Synonyms:
- GLUCOSE-6-PHOSPHATASE DEFICIENCY; GSD Ia; HEPATORENAL FORM OF GLYCOGEN STORAGE DISEASE; See all synonyms [MedGen]
- Identifiers:
- MONDO: MONDO:0009287; MedGen: C2919796; Orphanet: 364; Orphanet: 79258; OMIM: 232200
Assertion and evidence details
| Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
|---|---|---|---|---|---|---|
| SCV000033018 | OMIM | no assertion criteria provided | Pathogenic (Aug 30, 2004) | germline | literature only | |
| SCV000040456 | GeneReviews | no classification provided | not provided | germline | literature only | |
| SCV000223927 | Knight Diagnostic Laboratories, Oregon Health and Sciences University | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Dec 15, 2014) | germline | clinical testing | |
| SCV000402976 | Illumina Laboratory Services, Illumina | criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) | Pathogenic (Apr 27, 2017) | germline | clinical testing | |
| SCV000658103 | Labcorp Genetics (formerly Invitae), Labcorp | criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) | Pathogenic (Jan 24, 2026) | germline | clinical testing | |
| SCV000695636 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) | Pathogenic (May 13, 2016) | germline | clinical testing | PubMed (3) LabCorp Variant Classification Summary - May 2015.docx, |
| SCV000784537 | Genomic Research Center, Shahid Beheshti University of Medical Sciences | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Mar 5, 2018) | inherited | clinical testing | |
| SCV000894121 | Fulgent Genetics, Fulgent Genetics | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Oct 31, 2018) | unknown | clinical testing | |
| SCV000996289 | Pathology and Clinical Laboratory Medicine, King Fahad Medical City | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic | germline | clinical testing | |
| SCV001140451 | Mendelics | criteria provided, single submitter (Mendelics Assertion Criteria 2017) | Pathogenic (May 28, 2019) | unknown | clinical testing | |
| SCV001142473 | Reproductive Health Research and Development, BGI Genomics | no assertion criteria provided | Pathogenic (Jan 6, 2020) | germline | curation | |
| SCV001163780 | Baylor Genetics | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic | germline | clinical testing | |
| SCV001194060 | Myriad Genetics, Inc. | criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) | Pathogenic (Oct 18, 2019) | unknown | clinical testing | |
| SCV001244747 | Kids Research, The Children's Hospital at Westmead | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic | inherited | research | |
| SCV001463398 | Natera, Inc. | criteria provided, single submitter (Natera Variant Classification Schema (03/2026)) | Pathogenic (Nov 4, 2025) | germline | clinical testing | |
| SCV001469244 | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | no assertion criteria provided | Likely pathogenic (Oct 11, 2020) | germline | clinical testing | |
| SCV002023776 | Revvity Omics, Revvity | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Apr 2, 2025) | germline | clinical testing | |
| SCV002573306 | 3billion | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Oct 2, 2025) | germline | clinical testing | |
| SCV005051772 | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Feb 1, 2024) | germline | curation | |
| SCV005088759 | Breakthrough Genomics, Breakthrough Genomics | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Dec 8, 2021) | germline | clinical testing | |
| SCV005875332 | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) | Pathogenic (May 15, 2024) | germline | clinical testing | |
| SCV006302916 | Immunogenetics and Transplant Biology Service, University Hospital "Città della Salute e della Scienza di Torino" | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Jun 28, 2025) | germline | clinical testing |
Summary from all submissions
| Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
|---|---|---|---|---|---|---|---|---|
| not provided | germline | no | not provided | not provided | not provided | not provided | not provided | clinical testing, curation |
| not provided | germline | not provided | not provided | not provided | not provided | not provided | not provided | literature only |
| not provided | unknown | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing |
| not provided | germline | yes | not provided | not provided | not provided | not provided | not provided | clinical testing, literature only |
| not provided | germline | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing, curation |
| not provided | inherited | yes | 1 | not provided | not provided | not provided | not provided | clinical testing, research |
| Arab | germline | yes | 8 | not provided | not provided | not provided | not provided | clinical testing |
Citations
PubMed
Diagnosis of a novel glycogen storage disease: type 1aSP.
Burchell A, Waddell ID.
J Inherit Metab Dis. 1990;13(3):247-9. No abstract available.
- PMID:
- 2172641
Glycogen Storage Disease Type I..
Bali DS, El-Gharbawy A, Austin S, Pendyal S, Kishnani PS.
2006 Apr 19 [updated 2021 Oct 14]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026.
- PMID:
- 20301489
PMC
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee.
Genetics in medicine : official journal of the American College of Medical Genetics. 2015 May; 17(5): 405-24
- PMCID:
- PMC4544753
- PMID:
- 25741868
- DOI:
- 10.1038/gim.2015.30
Details of each submission
From OMIM, SCV000033018.3
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | literature only | PubMed (7) |
Description
Lei et al. (1993) concluded that a patient with type Ia glycogen storage disease (GSD1A; 232200) was a compound heterozygote for 2 different G6PC mutations: arg83-to-cys (R83C) and arg295-to-cys (R295C; 613742.0003), located in exons 2 and 5, respectively. The exon 5 mutation came from the father and the exon 2 mutation from the mother. Both mutations were thought to involve a CpG doublet. Lei et al. (1994) demonstrated that the R83C mutant has no detectable phosphohydrolase activity.
In a patient originally reported by Burchell and Waddell (1990) as having a novel form of type I glycogen storage disease due to a defect in the 21-kD stabilizing protein SP, Lei et al. (1995) demonstrated that in fact there was an R83C mutation in exon 2 of the G6PC gene. They found the same mutation in both homozygous and heterozygous form in patients with standard GSD type Ia.
Qu et al. (1996) performed prenatal diagnosis by chorionic villus sampling in an Ashkenazi Jewish family in which a previous child was homoallelic and both parents were heterozygous for the R83C mutation. Molecular analysis showed that the fetus was not affected.
Parvari et al. (1997) found that the R83C mutation was present in all Ashkenazi Jewish patients studied in Israel, suggesting that DNA-based diagnosis may be used as an initial diagnostic step in this population, thus avoiding liver biopsy.
Ekstein et al. (2004) tested 20,719 Ashkenazi Jewish subjects for the R83C mutation and identified 290 carriers, giving a carrier frequency of 0.014. The authors noted that this carrier frequency translates into a predicted disease prevalence of 1 in 20,000, 5 times higher than that for the general Caucasian population, confirming a founder effect and elevated frequency of type Ia glycogen storage disease in the Ashkenazi population. They also tested 4,290 Ashkenazi subjects for the Q347X (613742.0004) mutation and found no carriers. Of 30 Ashkenazi Jewish patients with type Ia glycogen storage disease, all were homozygous for the R83C mutation. Ekstein et al. (2004) concluded that R83C is the only prevalent mutation for this disease in the Ashkenazi population.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | not provided | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From GeneReviews, SCV000040456.3
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | literature only | not provided |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Knight Diagnostic Laboratories, Oregon Health and Sciences University, SCV000223927.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | no | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Illumina Laboratory Services, Illumina, SCV000402976.3
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (11) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Labcorp Genetics (formerly Invitae), Labcorp, SCV000658103.10
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (8) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000695636.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (3) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Genomic Research Center, Shahid Beheshti University of Medical Sciences, SCV000784537.3
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | inherited | yes | not provided | not provided | not provided | 1 | not provided | not provided | not provided | |
From Fulgent Genetics, Fulgent Genetics, SCV000894121.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | unknown | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Pathology and Clinical Laboratory Medicine, King Fahad Medical City, SCV000996289.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | Arab | 8 | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | 8 | not provided | not provided | not provided | |
From Mendelics, SCV001140451.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | unknown | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Reproductive Health Research and Development, BGI Genomics, SCV001142473.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | curation | not provided |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Baylor Genetics, SCV001163780.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Myriad Genetics, Inc., SCV001194060.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (8) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | unknown | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Kids Research, The Children's Hospital at Westmead, SCV001244747.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | research | PubMed (2) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | inherited | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Natera, Inc., SCV001463398.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (2) |
Description
The c.247C>T variant in G6PC1 is a missense variant predicted to cause substitution of arginine to cysteine at amino acid 83. This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 34946936, 12713862). Given the available evidence, this variant is classified as Pathogenic.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City, SCV001469244.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Revvity Omics, Revvity, SCV002023776.4
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From 3billion, SCV002573306.3
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (3) |
Description
The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.040%). Predicted Consequence/Location: Missense variant Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 8211187). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.83 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.95 (> 0.75, sensitivity 0.96 and precision 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011998 /PMID: 8211187 /3billion dataset). Different missense changes at the same codon (p.Arg83His, p.Arg83Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000038300, VCV002581673 /PMID: 7655466). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV005051772.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | curation | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | no | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Breakthrough Genomics, Breakthrough Genomics, SCV005088759.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
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].
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV005875332.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Immunogenetics and Transplant Biology Service, University Hospital "Città della Salute e della Scienza di Torino", SCV006302916.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
Last Updated: Jun 20, 2026