17-42911391-C-T

Position:

• chr17-42911391-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000151.4(G6PC1):​c.1039C>T​(p.Gln347Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000286 in 1,614,180 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: G6PC1 NM_000151.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:17 O:1
• Conservation: PhyloP100: 0.194

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-42911391-C-T is Pathogenic according to our data. Variant chr17-42911391-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-42911391-C-T is described in Lovd as [Pathogenic]. Variant chr17-42911391-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PC1	NM_000151.4	c.1039C>T	p.Gln347Ter	stop_gained	5/5	ENST00000253801.7
G6PC1	NM_001270397.2	c.*431C>T		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PC1	ENST00000253801.7	c.1039C>T	p.Gln347Ter	stop_gained	5/5	1	NM_000151.4	P1
G6PC1	ENST00000585489.1	c.*431C>T		3_prime_UTR_variant	4/4	5

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000456

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000204 AC: 51 AN: 250168 Hom.: 0 AF XY: 0.000214 AC XY: 29 AN XY: 135622

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.000116

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: 0.000389

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000291 AC: 425 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.000257 AC XY: 187 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000134

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: 0.000365

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74462

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000433 Hom.: 0

Bravo AF: 0.000227

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.000218

EpiControl AF: 0.000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Pathogenic:9 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Diagnostics Department, Viafet Genomics Laboratory	Aug 23, 2021	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	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 protein 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1994	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 25, 2017	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. -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 06, 2021	PVS1, PS4_moderate, PM2, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	G6PC1: PM3:Strong, PM2, PVS1:Moderate, PP1, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 07, 2015	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2021

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. -

G6PC1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 20, 2024

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. -

Glycogen storage disease Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

May 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	32
DANN	Benign	0.91
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.21	N
MutationTaster	Benign	1.0	A;A
Vest4		0.53
GERP RS		-1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs80356487; hg19: chr17-41063408;