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).
ClinVar Genomic variation as it relates to human health
NM_000151.4(G6PC1):c.1039C>T (p.Gln347Ter)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(18)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
18
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000151.4(G6PC1):c.1039C>T (p.Gln347Ter)
Variation ID: 12000 Accession: VCV000012000.55
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q21.31 17: 42911391 (GRCh38) [ NCBI UCSC ] 17: 41063408 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 29, 2016 Oct 20, 2024 Jan 29, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000151.4:c.1039C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000142.2:p.Gln347Ter nonsense NM_001270397.2:c.*431C>T 3 prime UTR NC_000017.11:g.42911391C>T NC_000017.10:g.41063408C>T NG_011808.1:g.15594C>T LRG_147:g.15594C>T LRG_147t1:c.1039C>T LRG_147p1:p.Gln347Ter NP_000142.1:p.Gln347Ter - Protein change
- Q347*
- Other names
-
G6PC, GLN347TER
p.Q347*:CAG>TAG
1118C>T
p.Gln347*
- Canonical SPDI
- NC_000017.11:42911390:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00023
The Genome Aggregation Database (gnomAD) 0.00026
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| G6PC1 | - | - |
GRCh38 GRCh37 |
568 | 575 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (10) |
criteria provided, multiple submitters, no conflicts
|
Jan 29, 2024 | RCV000012780.29 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2023 | RCV000199372.35 | |
| Pathogenic (1) |
no assertion criteria provided
|
May 20, 2019 | RCV001027894.2 | |
|
G6PC1-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
May 20, 2024 | RCV003398491.5 |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 17, 2021 | RCV004018616.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894123.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Aug 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
germline
|
Genetic Diagnostics Department, Viafet Genomics Laboratory
Accession: SCV001976440.1
First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
Comment:
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 … (more)
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). (less)
Number of individuals with the variant: 1
Secondary finding: yes
|
|
|
Pathogenic
(Nov 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001163792.2
First in ClinVar: Feb 28, 2020 Last updated: Mar 11, 2023 |
|
|
|
Pathogenic
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000776256.8
First in ClinVar: Jan 11, 2018 Last updated: Feb 14, 2024 |
Comment:
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, … (more)
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. (less)
|
|
|
Pathogenic
(Apr 07, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000230856.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 12
Sex: mixed
|
|
|
Pathogenic
(Sep 25, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease type 1A
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919368.1
First in ClinVar: May 31, 2019 Last updated: May 31, 2019 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Nov 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001194080.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
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, … (more)
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. (less)
|
|
|
Pathogenic
(Jun 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001762112.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
Clinical Features:
Hepatic steatosis (present) , Hyperuricemia (present) , Hypertriglyceridemia (present) , Hepatomegaly (present) , Hypercholesterolemia (present) , Lactic acidosis (present) , Short stature (present)
|
|
|
Pathogenic
(May 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000251525.15
First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023 |
Comment:
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, … (more)
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) (less)
|
|
|
Pathogenic
(May 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV003853549.1
First in ClinVar: Apr 09, 2023 Last updated: Apr 09, 2023 |
Comment:
PVS1, PS4_moderate, PM2, PP4
|
|
|
Pathogenic
(Nov 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003820021.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jul 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003737475.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Feb 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001334652.25
First in ClinVar: Jun 08, 2020 Last updated: Oct 20, 2024 |
Comment:
G6PC1: PM3:Strong, PM2, PVS1:Moderate, PP1, PS3:Supporting
Number of individuals with the variant: 5
|
|
|
Pathogenic
(May 01, 1994)
|
no assertion criteria provided
Method: literature only
|
GLYCOGEN STORAGE DISEASE Ia
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033020.3
First in ClinVar: Apr 04, 2013 Last updated: Jan 11, 2018 |
Comment on evidence:
In a patient with glycogen storage disease Ia (GSD1A; 232200), Lei et al. (1994) demonstrated compound heterozygosity for an arg83-to-cys mutation (613742.0002) in exon 2 … (more)
In a patient with glycogen storage disease Ia (GSD1A; 232200), Lei et al. (1994) demonstrated compound heterozygosity for an arg83-to-cys mutation (613742.0002) in exon 2 and a gln347-to-ter mutation in exon 5. The latter mutation was detected in homozygous form in 2 sibs of an unrelated family. The predicted Q347X mutant G6Pase is a truncated protein of 346 amino acids, 11 amino acids shorter than the wildtype G6Pase. Site-directed mutagenesis and transient expression assays demonstrated that the mutant protein is devoid of G6Pase activity. (less)
|
|
|
Pathogenic
(May 20, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Glycogen storage disease
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001190617.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Glycogen storage disease type Ia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001453363.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Pathogenic
(May 20, 2024)
|
no assertion criteria provided
Method: clinical testing
|
G6PC1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004120656.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000040455.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
|
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Comment:
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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)
Comment:
PVS1, PS4_moderate, PM2, PP4
Comment:
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.
Comment:
G6PC1: PM3:Strong, PM2, PVS1:Moderate, PP1, PS3:Supporting
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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).
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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)
Comment:
PVS1, PS4_moderate, PM2, PP4
Comment:
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.
Comment:
G6PC1: PM3:Strong, PM2, PVS1:Moderate, PP1, PS3:Supporting
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Glycogen Storage Disease Type I. | Adam MP | - | 2021 | PMID: 20301489 |
| The rs2229611 (G6PC:c.*23 T>C) is associated with glycogen storage disease type Ia in Brazilian patients. | Pinheiro FC | Molecular genetics and metabolism reports | 2020 | PMID: 33101979 |
| Genetic obesity: next-generation sequencing results of 1230 patients with obesity. | Kleinendorst L | Journal of medical genetics | 2018 | PMID: 29970488 |
| Glycogen storage disease type Ia: Adult presentation with microcytic anemia and liver adenomas. | Moest W | Hepatology (Baltimore, Md.) | 2018 | PMID: 29486517 |
| Clinical and biochemical heterogeneity between patients with glycogen storage disease type IA: the added value of CUSUM for metabolic control. | Peeks F | Journal of inherited metabolic disease | 2017 | PMID: 28397058 |
| Determining mutations in G6PC and SLC37A4 genes in a sample of Brazilian patients with glycogen storage disease types Ia and Ib. | Carlin MP | Genetics and molecular biology | 2013 | PMID: 24385852 |
| Development of genomic DNA reference materials for genetic testing of disorders common in people of ashkenazi jewish descent. | Kalman L | The Journal of molecular diagnostics : JMD | 2009 | PMID: 19815695 |
| Chromosomal and genetic alterations in human hepatocellular adenomas associated with type Ia glycogen storage disease. | Kishnani PS | Human molecular genetics | 2009 | PMID: 19762333 |
| Emerging therapies for glycogen storage disease type I. | Koeberl DD | Trends in endocrinology and metabolism: TEM | 2009 | PMID: 19541498 |
| Mutations in the glucose-6-phosphatase-alpha (G6PC) gene that cause type Ia glycogen storage disease. | Chou JY | Human mutation | 2008 | PMID: 18449899 |
| Type I glycogen storage diseases: disorders of the glucose-6-phosphatase complex. | Chou JY | Current molecular medicine | 2002 | PMID: 11949931 |
| Genetic heterogeneity of glycogen storage disease type Ia in France: a study of 48 patients. | Trioche P | Human mutation | 2000 | PMID: 11058903 |
| Identification of mutations in the glucose-6-phosphatase gene in Czech and Slovak patients with glycogen storage disease type ia, including novel mutations K76N, V166A and 540del5. | Kozák L | Human mutation | 2000 | PMID: 10874313 |
| Molecular genetic analysis of 40 patients with glycogen storage disease type Ia: 100% mutation detection rate and 5 novel mutations. | Seydewitz HH | Human mutation | 2000 | PMID: 10612834 |
| Enzymatic characterization of four new mutations in the glucose-6 phosphatase (G6PC) gene which cause glycogen storage disease type 1a. | Bruni N | Annals of human genetics | 1999 | PMID: 10738525 |
| Mutations in the glucose-6-phosphatase gene of 53 Italian patients with glycogen storage disease type Ia. | Stroppiano M | Journal of inherited metabolic disease | 1999 | PMID: 10070617 |
| Mutation analysis in 24 French patients with glycogen storage disease type 1a. | Chevalier-Porst F | Journal of medical genetics | 1996 | PMID: 8733042 |
| Genetic basis of glycogen storage disease type 1a: prevalent mutations at the glucose-6-phosphatase locus. | Lei KJ | American journal of human genetics | 1995 | PMID: 7573034 |
| Identification of mutations in the gene for glucose-6-phosphatase, the enzyme deficient in glycogen storage disease type 1a. | Lei KJ | The Journal of clinical investigation | 1994 | PMID: 8182131 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=G6PC | - | - | - | - |
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Text-mined citations for rs80356487 ...
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Record last updated Nov 25, 2024
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