rs80356479

Positions:

chr17-42900952-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 2.97

Variant links:

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]

G6PC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 154 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	UniProt
G6PC1	NM_000151.4 linkuse as main transcript	c.79del	p.Gln27ArgfsTer9	frameshift_variant	1/5	ENST00000253801.7
G6PC1	NM_001270397.2 linkuse as main transcript	c.79del	p.Gln27ArgfsTer9	frameshift_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PC1	ENST00000253801.7 linkuse as main transcript	c.79del	p.Gln27ArgfsTer9	frameshift_variant	1/5	1	NM_000151.4	P1	P35575-1
G6PC1	ENST00000592383.5 linkuse as main transcript	c.79del	p.Gln27ArgfsTer9	frameshift_variant	1/5	2			P35575-2
G6PC1	ENST00000585489.1 linkuse as main transcript	c.79del	p.Gln27ArgfsTer9	frameshift_variant	1/4	5
G6PC1	ENST00000588481.1 linkuse as main transcript	n.144del		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

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:

AN:

251486

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135916

show subpopulations

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.:

Cov.:

AF XY:

0.000172

AC XY:

125

AN XY:

727236

show subpopulations

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:

AN:

152274

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74448

show subpopulations

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:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease due to glucose-6-phosphatase deficiency type IA

Pathogenic:7Other: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(Q27Rfs9) 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(Q27Rfs9) 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 proteinâ€™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

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over