Variant summary: G6PC c.809G>T (p.Gly270Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251364 control chromosomes. c.809G>T has been widely reported in the literature in multiple individuals affected with Glycogen Storage Disease Type Ia (example, Lei_1995, Chevalier-Porst_1996, Parvari_1999, Allegrini_2017, Peeks_2017). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in complete abolishment of Glucose 6-phosphatase activity and accumulation of glycogen in liver (example, Lei_1995, Chevalier-Porst_1996). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000151.4(G6PC1):c.809G>T (p.Gly270Val)
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.
(10)
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
10
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.809G>T (p.Gly270Val)
Variation ID: 21063 Accession: VCV000021063.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 42911161 (GRCh38) [ NCBI UCSC ] 17: 41063178 (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 Feb 14, 2024 Apr 18, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000151.4:c.809G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000142.2:p.Gly270Val missense NM_001270397.2:c.*201G>T 3 prime UTR NC_000017.11:g.42911161G>T NC_000017.10:g.41063178G>T NG_011808.1:g.15364G>T LRG_147:g.15364G>T LRG_147t1:c.809G>T LRG_147p1:p.Gly270Val P35575:p.Gly270Val NP_000142.1:p.Gly270Val - Protein change
- G270V
- Other names
- -
- Canonical SPDI
- NC_000017.11:42911160:G:T
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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.
-
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
- 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 (9) |
criteria provided, multiple submitters, no conflicts
|
Apr 18, 2023 | RCV000239699.22 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 17, 2020 | RCV001551101.2 |
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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|---|---|---|---|---|---|
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Pathogenic
(Apr 20, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Von Gierke disease
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492901.1
First in ClinVar: Jan 12, 2017 Last updated: Jan 12, 2017 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163790.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
|
|
|
Pathogenic
(Jan 18, 2021)
|
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: SCV001478597.1
First in ClinVar: Feb 12, 2021 Last updated: Feb 12, 2021 |
Comment:
Variant summary: G6PC c.809G>T (p.Gly270Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: G6PC c.809G>T (p.Gly270Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251364 control chromosomes. c.809G>T has been widely reported in the literature in multiple individuals affected with Glycogen Storage Disease Type Ia (example, Lei_1995, Chevalier-Porst_1996, Parvari_1999, Allegrini_2017, Peeks_2017). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in complete abolishment of Glucose 6-phosphatase activity and accumulation of glycogen in liver (example, Lei_1995, Chevalier-Porst_1996). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Apr 17, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001771532.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
Published functional studies demonstrate a damaging effect: abolished enzyme activity (Lei et al., 1995; Shieh et al., 2002); Not observed at a significant frequency or … (more)
Published functional studies demonstrate a damaging effect: abolished enzyme activity (Lei et al., 1995; Shieh et al., 2002); Not observed at a significant frequency or in the homozygous state in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 10234610, 28659124, 7573034, 11739393, 28397058) (less)
|
|
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Likely pathogenic
(Mar 18, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000486040.2
First in ClinVar: Aug 29, 2016 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Apr 21, 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
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002779285.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
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Pathogenic
(Nov 10, 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: SCV002023773.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Apr 18, 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: SCV000829977.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects G6PC function (PMID: 7573034). Advanced modeling … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects G6PC function (PMID: 7573034). 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. ClinVar contains an entry for this variant (Variation ID: 21063). This missense change has been observed in individuals with glycogen storage disease (PMID: 7573034, 8733042, 10234610, 28397058, 28659124). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs80356483, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 270 of the G6PC protein (p.Gly270Val). (less)
|
|
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Pathogenic
(Aug 25, 2016)
|
no assertion criteria provided
Method: literature only
|
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
Affected status: yes
Allele origin:
germline
|
National Center for Biotechnology Information, National Institutes of Health
Accession: SCV000298096.1
First in ClinVar: Aug 29, 2016 Last updated: Aug 29, 2016
Comment:
Originally appeared in GeneReview for 'Glycogen Storage Disease Type I'; deleted from update of 8/25/2016.
|
|
|
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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: SCV002093325.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
Published functional studies demonstrate a damaging effect: abolished enzyme activity (Lei et al., 1995; Shieh et al., 2002); Not observed at a significant frequency or in the homozygous state in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 10234610, 28659124, 7573034, 11739393, 28397058)
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects G6PC function (PMID: 7573034). 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. ClinVar contains an entry for this variant (Variation ID: 21063). This missense change has been observed in individuals with glycogen storage disease (PMID: 7573034, 8733042, 10234610, 28397058, 28659124). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs80356483, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 270 of the G6PC protein (p.Gly270Val).
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:
Variant summary: G6PC c.809G>T (p.Gly270Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251364 control chromosomes. c.809G>T has been widely reported in the literature in multiple individuals affected with Glycogen Storage Disease Type Ia (example, Lei_1995, Chevalier-Porst_1996, Parvari_1999, Allegrini_2017, Peeks_2017). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in complete abolishment of Glucose 6-phosphatase activity and accumulation of glycogen in liver (example, Lei_1995, Chevalier-Porst_1996). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Published functional studies demonstrate a damaging effect: abolished enzyme activity (Lei et al., 1995; Shieh et al., 2002); Not observed at a significant frequency or in the homozygous state in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 10234610, 28659124, 7573034, 11739393, 28397058)
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects G6PC function (PMID: 7573034). 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. ClinVar contains an entry for this variant (Variation ID: 21063). This missense change has been observed in individuals with glycogen storage disease (PMID: 7573034, 8733042, 10234610, 28397058, 28659124). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs80356483, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 270 of the G6PC protein (p.Gly270Val).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Glycogen Storage Disease Type I. | Adam MP | - | 2021 | PMID: 20301489 |
| Cataract and optic disk drusen in a patient with glycogenosis and di George syndrome: clinical and molecular report. | Allegrini D | BMC ophthalmology | 2017 | PMID: 28659124 |
| 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 |
| Regression of hepatocellular adenomas with strict dietary therapy in patients with glycogen storage disease type I. | Beegle RD | JIMD reports | 2015 | PMID: 25308557 |
| Rapid screening of 12 common mutations in Turkish GSD 1a patients using electronic DNA microarray. | Eminoglu TF | Gene | 2013 | PMID: 23352793 |
| Type I glycogen storage diseases: disorders of the glucose-6-phosphatase complex. | Chou JY | Current molecular medicine | 2002 | PMID: 11949931 |
| 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 |
| Molecular genetics of type 1 glycogen storage disease. | Janecke AR | Molecular genetics and metabolism | 2001 | PMID: 11386847 |
| Glycogen storage disease type 1a in three siblings with the G270V mutation. | Parvari R | Journal of inherited metabolic disease | 1999 | PMID: 10234610 |
| Glycogen storage disease type Ia: four novel mutations (175delGG, R170X, G266V and V338F) identified. Mutations in brief no. 220. Online. | Rake JP | Human mutation | 1999 | PMID: 10094563 |
| 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 |
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Text-mined citations for rs80356483 ...
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.