ClinVar Miner

Submissions for variant NM_000151.4(G6PC):c.247C>T (p.Arg83Cys) (rs1801175)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 21
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000012778 SCV000223927 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2014-12-15 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000424594 SCV000227025 pathogenic not provided 2018-06-27 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000012778 SCV000402976 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2017-04-27 criteria provided, single submitter clinical testing The G6PC c.247C>T (p.Arg83Cys) variant is widely reported in the literature as a pathogenic variant for glycogen storage disease type I. The variant has been described in several studies as the most prevalent variant for this disease in the Ashkenazi Jewish population (Ekstein et al. 2004; Bali et al. 2006; Froissart et al. 2011). Across eight studies of individuals of different ethnic origins with glycogen storage disease type I, the p.Arg83Cys variant was reported in 35% (110/312) of alleles including at least 25 individuals in whom the variant was found in a homozygous state and seven in whom the variant was found in a compound heterozygous state (Lei et al. 1993; Lei et al. 1994; Lei et al. 1995; Parvari et al. 1997; Rake et al. 2000; Seydewitz et al. 2000; Sever et al. 2012; Carlin et al. 2013). All individuals showed significantly reduced or undetectable enzyme activity in liver biopsy samples. No control data were available from these studies, though the variant is reported at a frequency of 0.00090 in the European (non-Finnish) population of the Exome Aggregation Consortium. Transient expression studies of the variant by Lei et al. (1993) demonstrated that the p.Arg83Cys abolishes enzyme activity. Based on the collective evidence, the p.Arg83Cys variant is classified as pathogenic for glycogen storage disease type I. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000424594 SCV000520992 pathogenic not provided 2019-01-04 criteria provided, single submitter clinical testing The R83C variant in the G6PC gene has been reported previously as one of the most common variants causing GSD1a (Ekstein et al., 2004; Chou et al., 2008). The R83C variant is observed in 68/10,152 (0.67%) alleles from individuals of Ashkenazi Jewish background in large population cohorts, including one homozygote (Lek et al., 2016). The R83C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies have shown that R83C is associated with loss of glucose-6-phosphatase enzyme activity (Shieh et al., 2002). We interpret R83C as a pathogenic variant.
Invitae RCV000012778 SCV000658103 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2020-01-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 83 of the G6PC protein (p.Arg83Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs1801175, ExAC 0.09%), including one homozygous individual. This variant has been reported to segregate with glycogen storage disease type 1a in a single family (PMID: 8211187). It has also been reported as homozygous or in combination with another G6PC variant in individuals affected with glycogen storage disease type 1A, and in one case it was observed to be on the opposite chromosome (in trans) from another pathogenic variant (PMID: 23312056, 18008183, 15316959, 15316959, 7623438, 24385852, 10834516). This latter finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has been observed at particularly high frequency in the Ashkenazi Jewish subpopulation in both affected individuals and unaffected carriers (PMID: 15316959, 7623438, 25333069). This variant is also known as c.326C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 11998). Experimental studies have shown that this missense change severely reduces enzyme activity of the protein encoded by G6PC (PMID: 7744838). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000012778 SCV000695636 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2016-05-13 criteria provided, single submitter clinical testing Variant summary: The G6PC c.247C>T (p.Arg83Cys) variant involves the alteration of a conserved nucleotide resulting in a replacement of and Arginine with a Cystein located in the conserved phosphatase signature motif of G6PC. Mutations of the phosphatase active site residues are known to be clinically relevant; they predispose individuals to Glycogen Storage Disease (Clinvar, HGMD). Consistently, 5/5 in silico tools predict this variant to be deleterious. The variant was found in 64/121294 control chromosomes (1 homozygote) at a frequency of 0.0005276, which does not exceed the estimated maximal expected allele frequency of a pathogenic G6PC variant (0.0017321). It was reported in several GSD patients in either homozygosity or in compound heterozygosity with other pathogenic variant indicating a disease causing impact. A functional study demonstrated the variant to result in complete inactivation of the enzyme, confirming the importance of an intact Arg83 residue in G6Pase catalysis and further supporting pathogenicity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as Pathogenic. Taken together, this variant is classified as a Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000360229 SCV000712202 pathogenic Glycogen storage disease 2016-06-06 criteria provided, single submitter clinical testing The p.Arg83Cys variant in G6PC is the most frequent pathogenic variant implicate d in Glycogen storage disease type I in the Ashkenazi Jewish population (Parvari 1997, Lei 1995, Ekstein 2004). This variant has also been identified 0.09% (60/ 66,646) of European chromosomes by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org; dbSNP rs1801175). In vitro functional studies also p rovide evidence that the p.Arg83Cys variant may impact protein function (Lei 199 3). In summary, this variant meets our criteria to be classified as pathogenic f or Glycogen storage disease type I in an autosomal recessive manner based upon i ts identification in patients and functional impact.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626623 SCV000747324 pathogenic Short stature; Hypoglycemia 2017-01-01 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000012778 SCV000784537 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2018-03-05 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000012778 SCV000894121 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2018-10-31 criteria provided, single submitter clinical testing
Pathology and Clinical Laboratory Medicine,King Fahad Medical City RCV000012778 SCV000996289 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA criteria provided, single submitter clinical testing
Mendelics RCV000012778 SCV001140451 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2019-05-28 criteria provided, single submitter clinical testing
Baylor Genetics RCV000012778 SCV001163780 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000012778 SCV001194060 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2019-10-18 criteria provided, single submitter clinical testing NM_000151.3(G6PC):c.247C>T(R83C) is classified as pathogenic in the context of glycogen storage disease type Ia. Sources cited for classification include the following: PMID: 10874313, 12093795, 8734807, 7814621, 15316959, 24082139, 12373566, and 9332655. Classification of NM_000151.3(G6PC):c.247C>T(R83C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Kids Research, The Children's Hospital at Westmead RCV000012778 SCV001244747 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA criteria provided, single submitter research
CeGaT Praxis fuer Humangenetik Tuebingen RCV000424594 SCV001246604 pathogenic not provided 2017-10-01 criteria provided, single submitter clinical testing
OMIM RCV000012778 SCV000033018 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2004-08-30 no assertion criteria provided literature only
GeneReviews RCV000012778 SCV000040456 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2016-08-25 no assertion criteria provided literature only
Myriad Women's Health, Inc. RCV000012778 SCV000485167 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2015-12-18 no assertion criteria provided clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000424594 SCV000801484 pathogenic not provided 2017-09-21 no assertion criteria provided clinical testing
Reproductive Health Research and Development,BGI Genomics RCV000012778 SCV001142473 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2020-01-06 no assertion criteria provided curation NM_000151.3:c.247C>T is also known as c.326C>T in the literature. NM_000151.3:c.247C>T in the G6PC gene has an allele frequency of 0.007 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant has been reported to segregate with glycogen storage disease type 1a in a single family (PMID: 8211187) and has been reported as homozygous or in combination with another G6PC variant in individuals affected with glycogen storage disease type 1A (PMID: 23312056). Ekstein et al reported 30 Glycogen storage disease type Ia patient in Ashkenazi Jewish origin. All of them are homozygous of this variant (PMID: 15316959). Experimental studies have shown that this missense change severely reduces enzyme activity of the protein encoded by G6PC (PMID: 7744838). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PM3_Strong; PP4; PP1.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.