ClinVar Genomic variation as it relates to human health
NM_000151.4(G6PC1):c.229T>C (p.Trp77Arg)
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.229T>C (p.Trp77Arg)
Variation ID: 12001 Accession: VCV000012001.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 42901105 (GRCh38) [ NCBI UCSC ] 17: 41053122 (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 Mar 29, 2015 Feb 14, 2024 Oct 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000151.4:c.229T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000142.2:p.Trp77Arg missense NM_001270397.2:c.229T>C NP_001257326.1:p.Trp77Arg missense NC_000017.11:g.42901105T>C NC_000017.10:g.41053122T>C NG_011808.1:g.5308T>C LRG_147:g.5308T>C P35575:p.Trp77Arg - Protein change
- W77R
- Other names
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G6PC, TRP77ARG
- Canonical SPDI
- NC_000017.11:42901104:T:C
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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.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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 |
568 | 575 |
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 (5) |
criteria provided, multiple submitters, no conflicts
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Oct 17, 2023 | RCV000012781.20 |
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
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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
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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
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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
(Aug 02, 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
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001774622.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
Variant summary: G6PC c.229T>C (p.Trp77Arg) results in a non-conservative amino acid change located in the phosphatidic acid phosphate type 2/haloperoxidase domain (IPR000326) of the encoded … (more)
Variant summary: G6PC c.229T>C (p.Trp77Arg) results in a non-conservative amino acid change located in the phosphatidic acid phosphate type 2/haloperoxidase domain (IPR000326) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251312 control chromosomes. c.229T>C has been reported in the literature in multiple individuals affected with Glycogen Storage Disease Type Ia (example, Chevalier-Porst_1996, Terzioglu_2001, Miltenberger-Miltenyi_2005, Eminoglu_2013, Quackenbush_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal G6P'ase enzyme activity in vitro in an experimental system of COS-7 cells transfected with mutant constructs (example, Bruni_1999). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 17, 2023)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001201510.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 77 of the G6PC protein … (more)
This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 77 of the G6PC protein (p.Trp77Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GSD1a (PMID: 11916325, 16435186, 23352793, 29374762). ClinVar contains an entry for this variant (Variation ID: 12001). 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: 10738525, 11739393). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 19, 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
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV002060372.2
First in ClinVar: Jan 15, 2022 Last updated: Nov 29, 2022 |
Comment:
NM_000151.3(G6PC1):c.229T>C(W77R) is a missense variant classified as pathogenic in the context of glycogen storage disease type Ia. W77R has been observed in cases with relevant … (more)
NM_000151.3(G6PC1):c.229T>C(W77R) is a missense variant classified as pathogenic in the context of glycogen storage disease type Ia. W77R has been observed in cases with relevant disease (PMID: 8733042, 11916325, 16435186, 23352793, 29374762). Functional assessments of this variant are available in the literature (PMID: 10738525, 11739393). W77R has not been observed in population frequency databases. In summary, NM_000151.3(G6PC1):c.229T>C(W77R) is a missense variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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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: SCV002093296.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Pathogenic
(May 01, 1996)
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no assertion criteria provided
Method: literature only
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GLYCOGEN STORAGE DISEASE Ia
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033021.3
First in ClinVar: Apr 04, 2013 Last updated: Jan 11, 2018 |
Comment on evidence:
In a French patient with glycogen storage disease Ia (GSD1A; 232200), Chevalier-Porst et al. (1996) found compound heterozygosity for a W77R missense mutation in the … (more)
In a French patient with glycogen storage disease Ia (GSD1A; 232200), Chevalier-Porst et al. (1996) found compound heterozygosity for a W77R missense mutation in the G6PC gene. The mutation changed a nonpolar hydrophobic amino acid (tryptophan) to a basic one (arginine). The amino acid substitution resulted from a T-to-C transition of nucleotide 308 in exon 1. (less)
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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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Late presentation of glycogen storage disease types Ia and III in children with short stature and hepatomegaly. | Quackenbush D | Journal of pediatric endocrinology & metabolism : JPEM | 2018 | PMID: 29374762 |
Rapid screening of 12 common mutations in Turkish GSD 1a patients using electronic DNA microarray. | Eminoglu TF | Gene | 2013 | PMID: 23352793 |
Mutation spectrum of type I glycogen storage disease in Hungary. | Miltenberger-Miltenyi G | Journal of inherited metabolic disease | 2005 | PMID: 16435186 |
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 gene mutations in Turkish patients with glycogen storage disease type Ia. | Terzioglu M | Journal of inherited metabolic disease | 2001 | PMID: 11916325 |
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 |
Mutation analysis in 24 French patients with glycogen storage disease type 1a. | Chevalier-Porst F | Journal of medical genetics | 1996 | PMID: 8733042 |
Text-mined citations for rs104894566 ...
HelpRecord 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.