Submissions for variant NM_000151.4(G6PC1):c.1039C>T (p.Gln347Ter)

gnomAD frequency: 0.00026  dbSNP: rs80356487

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000199372	SCV000230856	pathogenic	not provided	2015-04-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000199372	SCV000251525	pathogenic	not provided	2022-05-12	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on enzyme function (Lei et al., 1994); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 11 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 24385852, 10874313, 8182131, 29970488, 28397058, 34093448, 31589614, 33101979, 24077912, 27535533, 34258141)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000012780	SCV000776256	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln347*) in the G6PC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acid(s) of the G6PC protein. This variant is present in population databases (rs80356487, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with glycogen storage disease type 1A (PMID: 7573034, 8182131, 8733042, 10070617, 11949931, 28397058). ClinVar contains an entry for this variant (Variation ID: 12000). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects G6PC function (PMID: 8182131). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000012780	SCV000894123	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012780	SCV000919368	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2017-09-25	criteria provided, single submitter	clinical testing	Variant summary: The G6PC c.1039C>T (p.Gln347X) variant results in a premature termination codon, predicted to cause a truncated or absent G6PC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 56/276802 control chromosomes at a frequency of 0.0002023, which does not exceed the estimated maximal expected allele frequency of a pathogenic G6PC variant (0.0017321). Multiple publications have cited the variant in affected compound heterozygote and homozygote individuals that had little to none glucose-6-phosphatase activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics	RCV000012780	SCV001163792	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2022-11-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000012780	SCV001194080	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2019-11-12	criteria provided, single submitter	clinical testing	NM_000151.3(G6PC):c.1039C>T(Q347*) is classified as pathogenic in the context of glycogen storage disease type Ia. Sources cited for classification include the following: PMID 8733042, 10738525, 19815695, 10874313, 24385852, 18449899, 7573034, 10070617 and 8182131. Classification of NM_000151.3(G6PC):c.1039C>T(Q347*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000199372	SCV001334652	pathogenic	not provided	2023-02-01	criteria provided, single submitter	clinical testing	G6PC1: PM3:Strong, PM2, PVS1:Moderate, PP1, PS3:Supporting
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000199372	SCV001762112	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Genetic Diagnostics Department, Viafet Genomics Laboratory	RCV000012780	SCV001976440	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2021-08-23	criteria provided, single submitter	clinical testing	As part of Carrier Screening testing performed at Viafet Genomics Laboratory, this variant was identified in a heterozygous state in a patient who is not affected with this condition. This variant is present in exon 5/5 in a position that is conserved across 1/2 transcripts of this gene. A loss-of-function variant is reported as disease-causing in HGMD and ClinVar after this position. This variant has been identified in a homozygous and compound heterozygous state in patients affected with Glycogen Storage Disease Ia (PMIDs: 8182131, 28397058, and 33101979). In addition, studies on biopsies from patients' liver cells have shown that this variant causes undetectable G6Pase Phosphohydrolase activity compared to the wildtype (PMIDs: 8182131 and 8733042).
Ambry Genetics	RCV004018616	SCV003737475	pathogenic	not specified	2021-07-17	criteria provided, single submitter	clinical testing	The c.1039C>T (p.Q347*) alteration, located in exon 5 (coding exon 5) of the G6PC gene, consists of a C to T substitution at nucleotide position 1039. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 347. This alteration occurs at the 3' terminus of the G6PC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 11 amino acids of the protein. However, premature stop codons are typically deleterious in nature. This mutation has been reported in the homozygous and compound heterozygous state in individuals with G6PC-related glycogen storage disease type I (Lei, 1994; Peeks, 2017). G6Pase was not detectable when this mutation was expressed in COS1 cells; it was also not detectable in liver biopsy samples of affected individuals homozygous or compound heterozygous for p.Q347* (Lei, 1994). Based on the available evidence, this alteration is classified as pathogenic.
Revvity Omics, Revvity	RCV000012780	SCV003820021	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2022-11-28	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000199372	SCV003853549	pathogenic	not provided	2024-06-20	criteria provided, single submitter	clinical testing	PM2, PVS1_strong
OMIM	RCV000012780	SCV000033020	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	1994-05-01	no assertion criteria provided	literature only
GeneReviews	RCV000012780	SCV000040455	not provided	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA		no assertion provided	literature only
Natera, Inc.	RCV001027894	SCV001190617	pathogenic	Glycogen storage disease	2019-05-20	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000012780	SCV001453363	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398491	SCV004120656	pathogenic	G6PC1-related disorder	2024-05-20	no assertion criteria provided	clinical testing	The G6PC1 c.1039C>T variant is predicted to result in premature protein termination (p.Gln347*). This variant has been well documented as causative for glycogen storage disease type Ia (e.g., Lei et al. 1994. PubMed ID 8182131; Chou and Mansfield. 2008. PubMed ID 18449899). This variant is reported in 0.038% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in G6PC1 are expected to be pathogenic. This variant is interpreted as pathogenic.