rs80356479

Positions:

• chr17-42900952-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000151.4(G6PC1):​c.79del​(p.Gln27ArgfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,614,142 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: G6PC1 NM_000151.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 2.97

Genes affected

G6PC1 (HGNC:4056): (glucose-6-phosphatase catalytic subunit 1) Glucose-6-phosphatase (G6Pase) is a multi-subunit integral membrane protein of the endoplasmic reticulum that is composed of a catalytic subunit and transporters for G6P, inorganic phosphate, and glucose. This gene (G6PC) is one of the three glucose-6-phosphatase catalytic-subunit-encoding genes in human: G6PC, G6PC2 and G6PC3. Glucose-6-phosphatase catalyzes the hydrolysis of D-glucose 6-phosphate to D-glucose and orthophosphate and is a key enzyme in glucose homeostasis, functioning in gluconeogenesis and glycogenolysis. Mutations in this gene cause glycogen storage disease type I (GSD1). This disease, also known as von Gierke disease, is a metabolic disorder characterized by severe hypoglycemia associated with the accumulation of glycogen and fat in the liver and kidneys.[provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 44 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-42900952-TC-T is Pathogenic according to our data. Variant chr17-42900952-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 21062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PC1	NM_000151.4	c.79del	p.Gln27ArgfsTer9	frameshift_variant	1/5	ENST00000253801.7	NP_000142.2
G6PC1	NM_001270397.2	c.79del	p.Gln27ArgfsTer9	frameshift_variant	1/5		NP_001257326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PC1	ENST00000253801.7	c.79del	p.Gln27ArgfsTer9	frameshift_variant	1/5	1	NM_000151.4	ENSP00000253801	P1
G6PC1	ENST00000592383.5	c.79del	p.Gln27ArgfsTer9	frameshift_variant	1/5	2		ENSP00000465958
G6PC1	ENST00000585489.1	c.79del	p.Gln27ArgfsTer9	frameshift_variant	1/4	5		ENSP00000466202
G6PC1	ENST00000588481.1	n.144del		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251486 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000174 AC: 255 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.000172 AC XY: 125 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000228

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74448

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000945

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Pathogenic:7 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The G6PC c.79delC (p.Gln27ArgfsTer9) variant results in a frameshift and is predicted to result in premature termination of the protein. The variant is also described in the literature as c.77delC or 158delC. Koeberl et al. (2009) describe the p.Gln27ArgfsTer9 variant as a common variant occurring in up to 5% of Caucasian individuals with glycogen storage disease type 1a. The p.Gln27ArgfsTer9 variant has been reported in five studies in which it is found in a total of 14 individuals including in seven in a homozygous state and seven in a compound heterozygous state (Chevalier-Porst et al. 1996; Rake et al. 1999; Shieh et al. 2002; Angaroni et al. 2004; Kishnani et al. 2009). The variant was additionally found in 7/192 disease alleles in two studies where zygosity data were not available (Lei et al. 1995; Seydewitz et al. 2000). Control data are unavailable for this variant which is reported at a frequency of 0.00235 in the African American population of the Exome Sequencing Project. Several studies report very low or undetectable enzyme activity in liver biopsy specimens indicating the inactivation of the enzyme by the p.Gln27ArgfsTer9 variant (Lei et al. 1995; Chevalier-Porst et al. 1996; Seydewitz et al. 2000; Rake et al. 1999). Chevalier-Porst et al. (1996) also described elevated glycogen content in the liver in an individual who was homozygous for the p.Gln27ArgfsTer9 variant. Based on the collective evidence, the p.Gln27ArgfsTer9 variant is classified as pathogenic for glycogen storage disease type 1. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2016	Variant summary: The G6PC c.79delC (p.Gln27Argfs) 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. One in silico tool predicts a damaging outcome for this variant. This variant was found in 8/121400 control chromosomes at a frequency of 0.0000659, which does not exceed the estimated maximal expected allele frequency of a pathogenic G6PC variant (0.0017321). There are multiple GSD1a patients reported in the literature who carried the variant as homozygous or heterozygous indicating the pathogenicity of the variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as Pathogenic. Taken together, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 15, 2019	NM_000151.3(G6PC):c.79delC(Q27Rfs*9) is classified as pathogenic in the context of type Ia glycogen storage disease. Sources cited for classification include the following: PMID 10834516, 12373566, 10874313, 20532819, 23352793, 7573034, 17994282 and 11949931. Classification of NM_000151.3(G6PC):c.79delC(Q27Rfs*9) 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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change creates a premature translational stop signal (p.Gln27Argfs*9) in the G6PC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in G6PC are known to be pathogenic (PMID: 8182131). This variant is present in population databases (rs768209865, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with glycogen storage disease (PMID: 10094563, 11739393, 16435186, 28397058). This variant is also known as 158delC. ClinVar contains an entry for this variant (Variation ID: 21062). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 16, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 01, 2014	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28283841, 10612834, 19541498, 23031489, 10094563, 15542400, 7573034, 34258141, 28397058, 8733042, 11739393, 19762333) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	G6PC1: PVS1:Strong, PM2, PM3, PP4:Moderate -

G6PC1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 22, 2024

The G6PC1 c.79delC variant is predicted to result in a frameshift and premature protein termination (p.Gln27Argfs*9). This variant has previously been reported in the homozygous and compound heterozygous state in multiple patients with glycogen storage disease type Ia (GSD Ia) (e.g., Lei et al. 1995. PubMed ID: 7573034; Chevalier-Porst et al. 1996. PubMed ID: 8733042, Rake et al. 1999. PubMed ID: 10094563). This variant has also been referred to as 158delC/35X in the literature. This variant is interpreted as likely pathogenic or pathogenic in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/21062). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in G6PC1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Glycogen storage disease, type I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 25, 2020

The p.Gln27ArgfsX9 variant in G6PC has been reported in at least 4 homozgyous and 2 compound heterozygous individuals with Glycogen storage disease, and reported without allele state information in an additional 6 individuals with Glycogen storage disease (Lei 1995 PMID: 7573034, Chevalier-Porst 1996 PMID: 8733042, Rake 1999 PMID: 10094563, Angaroni 2004 PMID: 15542400). It has also been identified in 0.011% (14/129190) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive allele frequency. This variant is reported in ClinVar (Variation ID: 21062). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 27 and leads to a premature termination codon 9 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the G6PC gene is an established disease mechanism in autosomal recessive Glycogen storage disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Glycogen storage disease. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80356479; hg19: chr17-41052969;