Variant summary: The G6PC c.248G>A (p.Arg83His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant, which was confirmed by a functional study showing p.Arg83His abolished G6Pase activity. This variant was found in 3/121296 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, predominantly in Chinese population. In addition, multiple reputable databases classified this variant as pathogenic. p.Arg83Cys has been shown to associate with GSD1a, suggesting Arg83 is a critical amino acid. Taken together, this variant is classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000151.4(G6PC1):c.248G>A (p.Arg83His)
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
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.248G>A (p.Arg83His)
Variation ID: 38300 Accession: VCV000038300.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 42903948 (GRCh38) [ NCBI UCSC ] 17: 41055965 (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 Aug 29, 2016 Sep 16, 2024 Jan 16, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000151.4:c.248G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000142.2:p.Arg83His missense NM_001270397.2:c.248G>A NP_001257326.1:p.Arg83His missense NC_000017.11:g.42903948G>A NC_000017.10:g.41055965G>A NG_011808.1:g.8151G>A LRG_147:g.8151G>A LRG_147t1:c.248G>A LRG_147p1:p.Arg83His P35575:p.Arg83His NP_000142.1:p.Arg83His - Protein change
- R83H
- Other names
- -
- Canonical SPDI
- NC_000017.11:42903947: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
- 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 (9) |
criteria provided, multiple submitters, no conflicts
|
Jan 16, 2024 | RCV000020132.21 |
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
(Dec 30, 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: SCV000695637.1
First in ClinVar: Aug 29, 2016 Last updated: Aug 29, 2016 |
Comment:
Variant summary: The G6PC c.248G>A (p.Arg83His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant, … (more)
Variant summary: The G6PC c.248G>A (p.Arg83His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant, which was confirmed by a functional study showing p.Arg83His abolished G6Pase activity. This variant was found in 3/121296 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, predominantly in Chinese population. In addition, multiple reputable databases classified this variant as pathogenic. p.Arg83Cys has been shown to associate with GSD1a, suggesting Arg83 is a critical amino acid. Taken together, this variant is classified as pathogenic. (less)
|
|
|
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: SCV001163781.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
|
|
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Pathogenic
(Dec 13, 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: SCV001193972.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000151.3(G6PC):c.248G>A(R83H) is classified as pathogenic in the context of glycogen storage disease type Ia. Sources cited for classification include the following: PMID 10944847, 7573034, 12373566, … (more)
NM_000151.3(G6PC):c.248G>A(R83H) is classified as pathogenic in the context of glycogen storage disease type Ia. Sources cited for classification include the following: PMID 10944847, 7573034, 12373566, 10748407, 7655466, 10797430 and 18449899. Classification of NM_000151.3(G6PC):c.248G>A(R83H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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|
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Pathogenic
(Feb 28, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
Affected status: yes
Allele origin:
germline
|
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital
Accession: SCV001739504.1
First in ClinVar: Jul 07, 2021 Last updated: Jul 07, 2021 |
Number of individuals with the variant: 1
Age: 0-9 years
Sex: male
Ethnicity/Population group: East asia
Geographic origin: China
Testing laboratory: Liwei's Lab
|
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Pathogenic
(May 03, 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
|
Revvity Omics, Revvity
Accession: SCV003820076.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Jan 16, 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: SCV000936720.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 83 of the G6PC protein (p.Arg83His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 83 of the G6PC protein (p.Arg83His). This variant is present in population databases (rs1801176, gnomAD 0.05%). This missense change has been observed in individuals with glycogen storage disease type Ia (PMID: 7573034, 10604148, 10797430). ClinVar contains an entry for this variant (Variation ID: 38300). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects G6PC function (PMID: 7573034). This variant disrupts the p.Arg83 amino acid residue in G6PC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7623438, 10834516, 15316959, 18008183, 23312056, 24385852). 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
(Mar 17, 2017)
|
no assertion criteria provided
Method: clinical testing
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Glycogen storage disease type Ia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002093298.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
Affected status: unknown
Allele origin:
germline
|
Medical Laboratory Center, Huzhou Maternal and Child Health Hospital
Accession: SCV004800929.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
|
|
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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: SCV000040457.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
NM_000151.3(G6PC):c.248G>A(R83H) is classified as pathogenic in the context of glycogen storage disease type Ia. Sources cited for classification include the following: PMID 10944847, 7573034, 12373566, 10748407, 7655466, 10797430 and 18449899. Classification of NM_000151.3(G6PC):c.248G>A(R83H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 83 of the G6PC protein (p.Arg83His). This variant is present in population databases (rs1801176, gnomAD 0.05%). This missense change has been observed in individuals with glycogen storage disease type Ia (PMID: 7573034, 10604148, 10797430). ClinVar contains an entry for this variant (Variation ID: 38300). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects G6PC function (PMID: 7573034). This variant disrupts the p.Arg83 amino acid residue in G6PC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7623438, 10834516, 15316959, 18008183, 23312056, 24385852). 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.
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: The G6PC c.248G>A (p.Arg83His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant, which was confirmed by a functional study showing p.Arg83His abolished G6Pase activity. This variant was found in 3/121296 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, predominantly in Chinese population. In addition, multiple reputable databases classified this variant as pathogenic. p.Arg83Cys has been shown to associate with GSD1a, suggesting Arg83 is a critical amino acid. Taken together, this variant is classified as pathogenic.
Comment:
NM_000151.3(G6PC):c.248G>A(R83H) is classified as pathogenic in the context of glycogen storage disease type Ia. Sources cited for classification include the following: PMID 10944847, 7573034, 12373566, 10748407, 7655466, 10797430 and 18449899. Classification of NM_000151.3(G6PC):c.248G>A(R83H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 83 of the G6PC protein (p.Arg83His). This variant is present in population databases (rs1801176, gnomAD 0.05%). This missense change has been observed in individuals with glycogen storage disease type Ia (PMID: 7573034, 10604148, 10797430). ClinVar contains an entry for this variant (Variation ID: 38300). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects G6PC function (PMID: 7573034). This variant disrupts the p.Arg83 amino acid residue in G6PC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7623438, 10834516, 15316959, 18008183, 23312056, 24385852). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Glycogen Storage Disease Type I. | Adam MP | - | 2021 | PMID: 20301489 |
| 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 |
| Glycogen storage disease type Ia: linkage of glucose, glycogen, lactic acid, triglyceride, and uric acid metabolism. | Sever S | Journal of clinical lipidology | 2012 | PMID: 23312056 |
| Mutations in the glucose-6-phosphatase-alpha (G6PC) gene that cause type Ia glycogen storage disease. | Chou JY | Human mutation | 2008 | PMID: 18449899 |
| Mutation spectrum of glycogen storage disease type Ia in Tunisia: implication for molecular diagnosis. | Barkaoui E | Journal of inherited metabolic disease | 2007 | PMID: 18008183 |
| Mutation frequencies for glycogen storage disease Ia in the Ashkenazi Jewish population. | Ekstein J | American journal of medical genetics. Part A | 2004 | PMID: 15316959 |
| Glycogen storage disease type I: diagnosis and phenotype/genotype correlation. | Matern D | European journal of pediatrics | 2002 | PMID: 12373566 |
| Glucose-6-phosphatase gene mutations in Taiwan Chinese patients with glycogen storage disease type Ia. | Chiang SC | Journal of human genetics | 2000 | PMID: 10944847 |
| 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 |
| Heterogeneous mutations in the glucose-6-phosphatase gene in Japanese patients with glycogen storage disease type Ia. | Takahashi K | American journal of medical genetics | 2000 | PMID: 10797430 |
| Glycogen storage disease type Ia: molecular diagnosis of 51 Japanese patients and characterization of splicing mutations by analysis of ectopically transcribed mRNA from lymphoblastoid cells. | Akanuma J | American journal of medical genetics | 2000 | PMID: 10748407 |
| Hypercalcaemia in glycogen storage disease type Ia: a case with R83H and 341delG mutations. | Hwu WL | Journal of inherited metabolic disease | 1999 | PMID: 10604148 |
| Genetic analysis of the glucose-6-phosphatase mutation of type 1a glycogen storage disease in a Chinese family. | Lee WJ | Clinical genetics | 1996 | PMID: 9001800 |
| Glucose-6-phosphatase gene G327A mutation is common in Chinese patients with glycogen storage disease type Ia. | Hwu WL | Human molecular genetics | 1995 | PMID: 7655466 |
| Characterization of the mutations in the glucose-6-phosphatase gene in Israeli patients with glycogen storage disease type 1a: R83C in six Jews and a novel V166G mutation in a Muslim Arab. | Parvari R | Journal of inherited metabolic disease | 1995 | PMID: 7623438 |
| 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 rs1801176 ...
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.