VCV000011998.73 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(28)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 11998 Accession: VCV000011998.73

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q21.31 17: 42903947 (GRCh38) [ NCBI UCSC ] 17: 41055964 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 5, 2015	Oct 20, 2024	Mar 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000151.4:c.247C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000142.2:p.Arg83Cys	missense
NM_001270397.2:c.247C>T	NP_001257326.1:p.Arg83Cys	missense
NC_000017.11:g.42903947C>T
NC_000017.10:g.41055964C>T
NG_011808.1:g.8150C>T
LRG_147:g.8150C>T
LRG_147t1:c.247C>T	LRG_147p1:p.Arg83Cys
	P35575:p.Arg83Cys
	NP_000142.1:p.Arg83Cys

... more HGVS ... less HGVS

Protein change

R83C

Other names

G6PC, ARG83CYS

Canonical SPDI

NC_000017.11:42903946:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00034

Trans-Omics for Precision Medicine (TOPMed) 0.00047

Exome Aggregation Consortium (ExAC) 0.00053

The Genome Aggregation Database (gnomAD), exomes 0.00057

Links

dbSNP: rs1801175 ClinGen: CA256177 Genetic Testing Registry (GTR): GTR000321629 UniProtKB: P35575#VAR_005239 OMIM: 613742.0002 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
G6PC1		-	-	GRCh38 GRCh37	568	575

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	Pathogenic (20)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000012778.46
Glycogen storage disease	Pathogenic (1)	criteria provided, single submitter	Jun 6, 2016	RCV000360229.7
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	May 1, 2023	RCV000424594.34
Hypoglycemia Short stature	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2017	RCV000626623.3
not specified	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 17, 2024	RCV003987317.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Dec 15, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease type 1A (Autosomal recessive inheritance) Affected status: no Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Accession: SCV000223927.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015
Pathogenic (Jan 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypoglycemia Short stature Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000747324.1 First in ClinVar: May 12, 2018 Last updated: May 12, 2018
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894121.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001163780.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020
Pathogenic (Jan 20, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000520992.6 First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000658103.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (7) PubMed: 7623438‚ 10834516‚ 15316959‚ 18008183‚ 23312056‚ 24385852‚ 7744838 Comment: 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 … (more) 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. (less)
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Affected status: no Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005051772.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (May 13, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000695636.1 First in ClinVar: Jan 11, 2018 Last updated: Jan 11, 2018	Publications: PubMed (3) PubMed: 11739393‚ 25308557‚ 11310582 Comment: 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 … (more) 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. (less)
Pathogenic (Jun 27, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000227025.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018	Publications: PubMed (2) PubMed: 28397058‚ 8211187 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=G6PC Number of individuals with the variant: 13 Sex: mixed
Pathogenic (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000402976.3 First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019	Publications: PubMed (11) PubMed: 24385852‚ 20301489‚ 8211187‚ 8182131‚ 7573034‚ 9332655‚ 10834516‚ 10612834‚ 15316959‚ 21599942‚ 23312056 Comment: 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 … (more) 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. (less)
Pathogenic (Jun 06, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Glycogen storage disease (Autosomal recessive inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000712202.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Publications: PubMed (2) PubMed: 15316959‚ 8211187 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Affected status: yes Allele origin: germline	Pathology and Clinical Laboratory Medicine, King Fahad Medical City Accession: SCV000996289.1 First in ClinVar: Oct 19, 2019 Last updated: Oct 19, 2019	Number of individuals with the variant: 8 Ethnicity/Population group: Arab Geographic origin: Middle East
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001140451.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Kids Research, The Children's Hospital at Westmead Accession: SCV001244747.1 First in ClinVar: May 04, 2020 Last updated: May 04, 2020	Publications: PubMed (1) PubMed: 32313153
Pathogenic (Oct 18, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001194060.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (8) PubMed: 10874313‚ 12093795‚ 8734807‚ 7814621‚ 15316959‚ 24082139‚ 12373566‚ 9332655 Comment: 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, … (more) 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. (less)
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Affected status: yes Allele origin: germline	3billion Accession: SCV002573306.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Comment: 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 … (more) 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. (less) Clinical Features: Abnormal hepatic glycogen storage (present) , Chronic diarrhea (present) , Bloody diarrhea (present) , Inflammation of the large intestine (present) , Abnormality of the immune … (more) Abnormal hepatic glycogen storage (present) , Chronic diarrhea (present) , Bloody diarrhea (present) , Inflammation of the large intestine (present) , Abnormality of the immune system (present) (less)
Pathogenic (Mar 05, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Affected status: yes Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000784537.2 First in ClinVar: May 26, 2018 Last updated: Dec 11, 2022	Number of individuals with the variant: 1 Age: 0-9 years Sex: female Geographic origin: Iran
Pathogenic (Jan 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002023776.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Mar 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004805179.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (Jun 03, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003549547.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (10) PubMed: 7573034‚ 8182131‚ 8211187‚ 12713862‚ 28397058‚ 29750741‚ 32313153‚ 33224545‚ 33763395‚ 34093448 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 29, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000801484.3 First in ClinVar: Aug 04, 2018 Last updated: Jun 09, 2024	Publications: PMID:8211187 PMID:8211187 15316959 15316959 18449899 18449899 24385852 24385852 12713862 12713862 23312056 23312056 25333069 25333069 24082139 24082139 Comment: PS3, PS4_moderate, PM1, PM2, PP1, PP5 Number of individuals with the variant: 6
Pathogenic (Dec 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005088759.2 First in ClinVar: Aug 04, 2024 Last updated: Aug 25, 2024	Comment: 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 … (more) 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]. (less)
Pathogenic (May 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246604.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: G6PC1: PM3:Very Strong, PM1, PM5, PP4:Moderate, PS3:Moderate, PM2:Supporting, PP3 Number of individuals with the variant: 6
Pathogenic (Aug 30, 2004)	no assertion criteria provided Method: literature only	GLYCOGEN STORAGE DISEASE Ia Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033018.3 First in ClinVar: Apr 04, 2013 Last updated: Jan 11, 2018	Publications: PubMed (7) PubMed: 8211187‚ 8182131‚ 2172641‚ 7573034‚ 8734807‚ 9332655‚ 15316959 Comment on evidence: 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: … (more) 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. (less)
Likely pathogenic (Oct 11, 2020)	no assertion criteria provided Method: clinical testing	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001469244.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021
Pathogenic (Jan 06, 2020)	no assertion criteria provided Method: curation	Glycogen storage disease type 1A Affected status: unknown Allele origin: germline	Reproductive Health Research and Development, BGI Genomics Accession: SCV001142473.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020	Comment: 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 … (more) 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. (less)
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Glycogen storage disease type Ia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001463398.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
not provided (-)	no classification provided Method: literature only	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000040456.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1312 BookShelf: NBK1312
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Comment:

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)

Comment:

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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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].

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Neurological Characteristics of Pediatric Glycogen Storage Disease.	Muzetti JH	Frontiers in endocrinology	2021	PMID: 34093448
Clinical and Genetic Spectra of Inherited Liver Disease in Children in China.	Fang Y	Frontiers in pediatrics	2021	PMID: 33763395
Glycogen Storage Disease Type I.	Adam MP	-	2021	PMID: 20301489
A Rare Case of Glycogen Storage Disease Type 1a Presenting with Hemophagocytic Lymphohistiocytosis (HLH).	Saneifard H	Case reports in pediatrics	2020	PMID: 33224545
The diagnostic utility of genome sequencing in a pediatric cohort with suspected mitochondrial disease.	Riley LG	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 32313153
Hemophagocytic Lymphohystiocytosis Associated With Type Ia Glycogen Storage Disease.	Düzenli Kar Y	Journal of pediatric hematology/oncology	2019	PMID: 29750741
Clinical and biochemical heterogeneity between patients with glycogen storage disease type IA: the added value of CUSUM for metabolic control.	Peeks F	Journal of inherited metabolic disease	2017	PMID: 28397058
Regression of hepatocellular adenomas with strict dietary therapy in patients with glycogen storage disease type I.	Beegle RD	JIMD reports	2015	PMID: 25308557
Disease variants in genomes of 44 centenarians.	Freudenberg-Hua Y	Molecular genetics & genomic medicine	2014	PMID: 25333069
Determining mutations in G6PC and SLC37A4 genes in a sample of Brazilian patients with glycogen storage disease types Ia and Ib.	Carlin MP	Genetics and molecular biology	2013	PMID: 24385852
Personalized genomic disease risk of volunteers.	Gonzalez-Garay ML	Proceedings of the National Academy of Sciences of the United States of America	2013	PMID: 24082139
Glycogen storage disease type Ia: linkage of glucose, glycogen, lactic acid, triglyceride, and uric acid metabolism.	Sever S	Journal of clinical lipidology	2012	PMID: 23312056
Glucose-6-phosphatase deficiency.	Froissart R	Orphanet journal of rare diseases	2011	PMID: 21599942
Mutations in the glucose-6-phosphatase-alpha (G6PC) gene that cause type Ia glycogen storage disease.	Chou JY	Human mutation	2008	PMID: 18449899
Mutation spectrum of glycogen storage disease type Ia in Tunisia: implication for molecular diagnosis.	Barkaoui E	Journal of inherited metabolic disease	2007	PMID: 18008183
Mutation frequencies for glycogen storage disease Ia in the Ashkenazi Jewish population.	Ekstein J	American journal of medical genetics. Part A	2004	PMID: 15316959
Gouty tendinitis revealing glycogen storage disease Type Ia in two adolescents.	Carvès C	Joint bone spine	2003	PMID: 12713862
Glycogen storage disease type I: diagnosis and phenotype/genotype correlation.	Matern D	European journal of pediatrics	2002	PMID: 12373566
The catalytic center of glucose-6-phosphatase. HIS176 is the nucleophile forming the phosphohistidine-enzyme intermediate during catalysis.	Ghosh A	The Journal of biological chemistry	2002	PMID: 12093795
The molecular basis of glycogen storage disease type 1a: structure and function analysis of mutations in glucose-6-phosphatase.	Shieh JJ	The Journal of biological chemistry	2002	PMID: 11739393
Glycogen storage disease type Ia: molecular study in Brazilian patients.	de C Reis F	Journal of human genetics	2001	PMID: 11310582
Identification of mutations in the glucose-6-phosphatase gene in Czech and Slovak patients with glycogen storage disease type ia, including novel mutations K76N, V166A and 540del5.	Kozák L	Human mutation	2000	PMID: 10874313
Glycogen storage disease type Ia: recent experience with mutation analysis, a summary of mutations reported in the literature and a newly developed diagnostic flow chart.	Rake JP	European journal of pediatrics	2000	PMID: 10834516
Molecular genetic analysis of 40 patients with glycogen storage disease type Ia: 100% mutation detection rate and 5 novel mutations.	Seydewitz HH	Human mutation	2000	PMID: 10612834
Glycogen storage disease type 1a in Israel: biochemical, clinical, and mutational studies.	Parvari R	American journal of medical genetics	1997	PMID: 9332655
Molecular prenatal diagnosis of glycogen storage disease type Ia.	Qu Y	Prenatal diagnosis	1996	PMID: 8734807
Mutations in the glucose-6-phosphatase gene are associated with glycogen storage disease types 1a and 1aSP but not 1b and 1c.	Lei KJ	The Journal of clinical investigation	1995	PMID: 7814621
Structure-function analysis of human glucose-6-phosphatase, the enzyme deficient in glycogen storage disease type 1a.	Lei KJ	The Journal of biological chemistry	1995	PMID: 7744838
Characterization of the mutations in the glucose-6-phosphatase gene in Israeli patients with glycogen storage disease type 1a: R83C in six Jews and a novel V166G mutation in a Muslim Arab.	Parvari R	Journal of inherited metabolic disease	1995	PMID: 7623438
Genetic basis of glycogen storage disease type 1a: prevalent mutations at the glucose-6-phosphatase locus.	Lei KJ	American journal of human genetics	1995	PMID: 7573034
Identification of mutations in the gene for glucose-6-phosphatase, the enzyme deficient in glycogen storage disease type 1a.	Lei KJ	The Journal of clinical investigation	1994	PMID: 8182131
Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a.	Lei KJ	Science (New York, N.Y.)	1993	PMID: 8211187
Diagnosis of a novel glycogen storage disease: type 1aSP.	Burchell A	Journal of inherited metabolic disease	1990	PMID: 2172641
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=G6PC	-	-	-	-
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Text-mined citations for rs1801175 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1801175 ...