The G6PC c.883C>T (p.Arg295Cys) variant was reported in a compound heterozygous state with a second variant in two individuals with glycogen storage disease (GSD) type I and in five alleles from individuals with the disorder (Lei et al. 1993; Lei et al 1995; Stroppiano et al. 1999; Kozak et al. 2000; Matern et al. 2002; Di Rocco et al. 2008). The variant was absent from a total of 14 healthy control individuals but is reported at a frequency of 0.00002 in the Total population of the Exome Aggregation Consortium. Functional studies by Lei et al. (1993) showed that phosphohydrolase activity was abolished in COS1 cells expressing the p.Arg295Cys variant, while research by Shieh et al. (2002) suggested that the p.Arg295Cys variant could cause misfolding and protein degradation. Based on the evidence, the p.Arg295Cys variant is classified as likely pathogenic for glycogen storage disease type I. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ClinVar Genomic variation as it relates to human health
NM_000151.4(G6PC1):c.883C>T (p.Arg295Cys)
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.
(9)
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/Likely pathogenic
9
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.883C>T (p.Arg295Cys)
Variation ID: 11999 Accession: VCV000011999.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 42911235 (GRCh38) [ NCBI UCSC ] 17: 41063252 (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 Mar 29, 2015 Feb 14, 2024 Sep 28, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000151.4:c.883C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000142.2:p.Arg295Cys missense NM_001270397.2:c.*275C>T 3 prime UTR NC_000017.11:g.42911235C>T NC_000017.10:g.41063252C>T NG_011808.1:g.15438C>T LRG_147:g.15438C>T LRG_147t1:c.883C>T P35575:p.Arg295Cys - Protein change
- R295C
- Other names
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G6PC, ARG295CYS
- Canonical SPDI
- NC_000017.11:42911234:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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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.
-
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
- 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/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Sep 28, 2023 | RCV000012779.23 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 22, 2022 | RCV000725438.5 |
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. |
|
|---|---|---|---|---|---|
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Likely pathogenic
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000402984.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The G6PC c.883C>T (p.Arg295Cys) variant was reported in a compound heterozygous state with a second variant in two individuals with glycogen storage disease (GSD) type … (more)
The G6PC c.883C>T (p.Arg295Cys) variant was reported in a compound heterozygous state with a second variant in two individuals with glycogen storage disease (GSD) type I and in five alleles from individuals with the disorder (Lei et al. 1993; Lei et al 1995; Stroppiano et al. 1999; Kozak et al. 2000; Matern et al. 2002; Di Rocco et al. 2008). The variant was absent from a total of 14 healthy control individuals but is reported at a frequency of 0.00002 in the Total population of the Exome Aggregation Consortium. Functional studies by Lei et al. (1993) showed that phosphohydrolase activity was abolished in COS1 cells expressing the p.Arg295Cys variant, while research by Shieh et al. (2002) suggested that the p.Arg295Cys variant could cause misfolding and protein degradation. Based on the evidence, the p.Arg295Cys variant is classified as likely pathogenic for glycogen storage disease type I. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Likely pathogenic
(Sep 17, 2021)
|
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: SCV002785243.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
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Pathogenic
(Jun 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004228179.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
PP4, PM2, PM3, PS3, PS4_moderate
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Sep 28, 2023)
|
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: SCV000830993.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 295 of the G6PC protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 295 of the G6PC protein (p.Arg295Cys). This variant is present in population databases (rs104894563, gnomAD 0.007%). This missense change has been observed in individual(s) with glycogen storage disease type la (PMID: 8211187, 10070617, 12373566, 18083610). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.962C>T. ClinVar contains an entry for this variant (Variation ID: 11999). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt G6PC protein function. Experimental studies have shown that this missense change affects G6PC function (PMID: 8211187, 11739393). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Jul 08, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695633.1
First in ClinVar: Jan 11, 2018 Last updated: Jan 11, 2018 |
Comment:
Variant summary: The G6PC c.883C>T (p.Arg295Cys) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. … (more)
Variant summary: The G6PC c.883C>T (p.Arg295Cys) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/121408 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic G6PC variant (0.0017321). This variant has been reported in numerous GSD1a patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
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Pathogenic
(Nov 13, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000336926.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
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Likely pathogenic
(Sep 18, 2014)
|
criteria provided, single submitter
Method: literature only
|
Glycogen storage disease type 1A
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220708.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
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Pathogenic
(Oct 22, 1993)
|
no assertion criteria provided
Method: literature only
|
GLYCOGEN STORAGE DISEASE Ia
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033019.2
First in ClinVar: Apr 04, 2013 Last updated: Jan 11, 2018 |
Comment on evidence:
For discussion of the arg295-to-cys (R295C) mutation in the GSD1A gene that was found in compound heterozygous state in a patient with glycogen storage disease … (more)
For discussion of the arg295-to-cys (R295C) mutation in the GSD1A gene that was found in compound heterozygous state in a patient with glycogen storage disease Ia (GSD1A; 232200) by Lei et al. (1993), see 613742.0002. (less)
|
|
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Pathogenic
(Mar 17, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Glycogen storage disease type Ia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002093326.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
PP4, PM2, PM3, PS3, PS4_moderate
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 295 of the G6PC protein (p.Arg295Cys). This variant is present in population databases (rs104894563, gnomAD 0.007%). This missense change has been observed in individual(s) with glycogen storage disease type la (PMID: 8211187, 10070617, 12373566, 18083610). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.962C>T. ClinVar contains an entry for this variant (Variation ID: 11999). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt G6PC protein function. Experimental studies have shown that this missense change affects G6PC function (PMID: 8211187, 11739393). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: The G6PC c.883C>T (p.Arg295Cys) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/121408 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic G6PC variant (0.0017321). This variant has been reported in numerous GSD1a patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified 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:
The G6PC c.883C>T (p.Arg295Cys) variant was reported in a compound heterozygous state with a second variant in two individuals with glycogen storage disease (GSD) type I and in five alleles from individuals with the disorder (Lei et al. 1993; Lei et al 1995; Stroppiano et al. 1999; Kozak et al. 2000; Matern et al. 2002; Di Rocco et al. 2008). The variant was absent from a total of 14 healthy control individuals but is reported at a frequency of 0.00002 in the Total population of the Exome Aggregation Consortium. Functional studies by Lei et al. (1993) showed that phosphohydrolase activity was abolished in COS1 cells expressing the p.Arg295Cys variant, while research by Shieh et al. (2002) suggested that the p.Arg295Cys variant could cause misfolding and protein degradation. Based on the evidence, the p.Arg295Cys variant is classified as likely pathogenic for glycogen storage disease type I. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
PP4, PM2, PM3, PS3, PS4_moderate
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 295 of the G6PC protein (p.Arg295Cys). This variant is present in population databases (rs104894563, gnomAD 0.007%). This missense change has been observed in individual(s) with glycogen storage disease type la (PMID: 8211187, 10070617, 12373566, 18083610). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.962C>T. ClinVar contains an entry for this variant (Variation ID: 11999). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt G6PC protein function. Experimental studies have shown that this missense change affects G6PC function (PMID: 8211187, 11739393). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: The G6PC c.883C>T (p.Arg295Cys) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/121408 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic G6PC variant (0.0017321). This variant has been reported in numerous GSD1a patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Hepatocellular adenoma and metabolic balance in patients with type Ia glycogen storage disease. | Di Rocco M | Molecular genetics and metabolism | 2008 | PMID: 18083610 |
| Glycogen storage disease type I: diagnosis and phenotype/genotype correlation. | Matern D | European journal of pediatrics | 2002 | PMID: 12373566 |
| The molecular basis of glycogen storage disease type 1a: structure and function analysis of mutations in glucose-6-phosphatase. | Shieh JJ | The Journal of biological chemistry | 2002 | PMID: 11739393 |
| 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 |
| 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 |
| 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 |
| Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a. | Lei KJ | Science (New York, N.Y.) | 1993 | PMID: 8211187 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=G6PC | - | - | - | - |
Text-mined citations for rs104894563 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.