ClinVar Genomic variation as it relates to human health
NM_000151.4(G6PC1):c.562G>A (p.Gly188Ser)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000151.4(G6PC1):c.562G>A (p.Gly188Ser)
Variation ID: 214465 Accession: VCV000214465.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 42909418 (GRCh38) [ NCBI UCSC ] 17: 41061435 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Dec 6, 2016 May 12, 2024 Jan 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000151.4:c.562G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000142.2:p.Gly188Ser missense NM_001270397.2:c.485G>A NP_001257326.1:p.Arg162Lys missense NC_000017.11:g.42909418G>A NC_000017.10:g.41061435G>A NG_011808.1:g.13621G>A LRG_147:g.13621G>A LRG_147t1:c.562G>A - Protein change
- G188S, R162K
- Other names
- p.G188S:GGC>AGC
- Canonical SPDI
- NC_000017.11:42909417:G:A
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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G6PC1 | - | - |
GRCh38 GRCh37 |
560 | 566 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 1, 2023 | RCV000197003.10 | |
Pathogenic/Likely pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Jan 17, 2024 | RCV000587142.20 |
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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Pathogenic
(Apr 04, 2016)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695638.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant Summary: The variant of interest causes a missense change involving a conserved nucleotide 5/5 in silico programs predicting a "deleterious" outcome. The variant of … (more)
Variant Summary: The variant of interest causes a missense change involving a conserved nucleotide 5/5 in silico programs predicting a "deleterious" outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121410, which does not exceed the predicted maximum expected allele frequency for a pathogenic G6PC variant of 1/577. The variant of interest has been reported in affected individuals via publications, along with a reputable clinical laboratory citing the variant as "pathogenic." In addition, multiple functional studies indicate the variant to inactivate G6Pase enzyme activity. Furthermore, another variant at this position, c.562G>C (p.Gly188Arg) has been reported as pathogenic. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic. (less)
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Pathogenic
(Oct 17, 2016)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000251527.9
First in ClinVar: Oct 11, 2015 Last updated: Dec 06, 2016 |
Comment:
The G188S missense pathogenic variant in the G6PC gene has been reported previously in association with glycogen storage disease type 1a (Lei et al., 1995). … (more)
The G188S missense pathogenic variant in the G6PC gene has been reported previously in association with glycogen storage disease type 1a (Lei et al., 1995). Expression studies found that the G188S mutation abolishes G6Pase activity (Lei et al., 1995). Furthermore, G188S is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and another missense mutation at the same position (G188R) has also been reported in association with glycogen storage disease type 1a. Therefore, we interpret G188S to be a pathogenic variant. The variant is found in MITONUC-MITOP panel(s). (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163786.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: research
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Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
Affected status: no
Allele origin:
germline
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UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251515.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Comment:
carrier finding
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Comment:
The c.562G>A (p.G188S) missense variant has been reported in individuals with glycogen storage disease type Ia (PMID: 7573034; 12373566; 24565827).
Number of individuals with the variant: 1
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Pathogenic
(Jul 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556438.2
First in ClinVar: Aug 04, 2022 Last updated: Dec 17, 2022 |
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Likely pathogenic
(Apr 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002810635.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Jun 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003833776.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 17, 2024)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000776252.7
First in ClinVar: Mar 17, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 188 of the G6PC protein (p.Gly188Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 188 of the G6PC protein (p.Gly188Ser). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is present in population databases (rs80356482, gnomAD 0.004%). This missense change has been observed in individuals with glycogen storage disease type 1A (PMID: 7573034, 24565827; Invitae). This variant is also known as c.641G>A or G641A. ClinVar contains an entry for this variant (Variation ID: 214465). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects G6PC function (PMID: 11739393). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Gly188 amino acid residue in G6PC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8733042, 10834516, 10960498, 11739393). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004009791.7
First in ClinVar: Jul 16, 2023 Last updated: May 12, 2024 |
Comment:
G6PC1: PM2, PM5, PP4:Moderate, PS3:Moderate, PM3:Supporting, PP3
Number of individuals with the variant: 2
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Likely pathogenic
(May 14, 2017)
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no assertion criteria provided
Method: clinical testing
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Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000791230.2
First in ClinVar: Mar 17, 2018 Last updated: Dec 23, 2019 |
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Pathogenic
(Mar 17, 2017)
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no assertion criteria provided
Method: clinical testing
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Glycogen storage disease type Ia
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002093313.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Molecular mechanisms of neutrophil dysfunction in glycogen storage disease type Ib. | Jun HS | Blood | 2014 | PMID: 24565827 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
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 |
Glucose-6-phosphatase mutation G188R confers an atypical glycogen storage disease type 1b phenotype. | Weston BW | Pediatric research | 2000 | PMID: 10960498 |
Glycogen storage disease type Ia: recent experience with mutation analysis, a summary of mutations reported in the literature and a newly developed diagnostic flow chart. | Rake JP | European journal of pediatrics | 2000 | PMID: 10834516 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
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 |
Text-mined citations for rs80356482 ...
HelpRecord last updated May 12, 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.