ClinVar Genomic variation as it relates to human health
NM_000151.4(G6PC1):c.648G>T (p.Leu216=)
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.648G>T (p.Leu216=)
Variation ID: 12003 Accession: VCV000012003.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 42911000 (GRCh38) [ NCBI UCSC ] 17: 41063017 (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 Aug 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000151.4:c.648G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000142.2:p.Leu216= synonymous NM_001270397.2:c.*40G>T 3 prime UTR NC_000017.11:g.42911000G>T NC_000017.10:g.41063017G>T NG_011808.1:g.15203G>T LRG_147:g.15203G>T LRG_147t1:c.648G>T - Protein change
- Other names
- G6PC, IVS4, G-T, +86
- G727T
- IVS4AS, G-T, +86
- Canonical SPDI
- NC_000017.11:42910999:G: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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00009
- Links
- Comment on variant
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 |
567 | 573 |
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/Likely pathogenic (12) |
criteria provided, multiple submitters, no conflicts
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Jan 28, 2024 | RCV000012783.29 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 11, 2024 | RCV000723833.7 |
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
(Mar 18, 2016)
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criteria provided, single submitter
Method: reference population
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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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Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Accession: SCV000267328.1
First in ClinVar: Aug 29, 2016 Last updated: Aug 29, 2016 |
Number of individuals with the variant: 1
Age: 40-69 years
Ethnicity/Population group: East Asian
Geographic origin: South Korean
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Pathogenic
(Mar 22, 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: yes
Allele origin:
germline
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3billion
Accession: SCV002318566.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
Synonymous variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID: 7668282, … (more)
Synonymous variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID: 7668282, PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000012003, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000873). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 23000067, 11851840). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Proteinuria (present) , Stage 3 chronic kidney disease (present) , Gout (present)
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Pathogenic
(Mar 18, 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: SCV002781326.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 19, 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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Revvity Omics, Revvity
Accession: SCV002023772.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 28, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000942632.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects codon 216 of the G6PC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more)
This sequence change affects codon 216 of the G6PC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the G6PC protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs80356484, gnomAD 0.1%). This variant has been observed in individual(s) with glycogen storage disease type 1 (PMID: 7668282, 10797430, 23000067, 23486339, 24980439; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as g727t. ClinVar contains an entry for this variant (Variation ID: 12003). Studies have shown that this variant results in partial deletion of exon 5 and introduces a new termination codon (PMID: 7668282, 10748407). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 23, 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: SCV000695640.1
First in ClinVar: Jan 15, 2018 Last updated: Jan 15, 2018 |
Comment:
Variant summary: The G6PC c.648G>T (p.Leu216Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a … (more)
Variant summary: The G6PC c.648G>T (p.Leu216Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant may strengthen a cryptic 3' splicing acceptor site in exon 5. ESE finder predicts that this variant may create a novel SRp40 binding site. These predictions have been confirmed by at least one functional study (Kajihara_1995), showing this variant leads to a deletion of the front 91 nt of exon 5 in the patient's cDNA and this deletion results in a premature stop codon. This variant was found in 11/121428 control chromosomes at a frequency of 0.0000906, which does not exceed the estimated maximal expected allele frequency of a pathogenic G6PC variant (0.0017321). This variant has been reported as the most common pathogenic variant in GSD1a patients in East Asia. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Feb 20, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000230857.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Jan 11, 2019)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000915764.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The G6PC c.648G>T (p.Leu216Leu) synonymous variant is an established pathogenic variant that occurs in approximately 91% of Japanese glucogen storage disease type 1 (GSD1) alleles, … (more)
The G6PC c.648G>T (p.Leu216Leu) synonymous variant is an established pathogenic variant that occurs in approximately 91% of Japanese glucogen storage disease type 1 (GSD1) alleles, 75% of Korean GSD1 alleles, and 54% of Chinese GSD1 alleles (Chou et al. 2008; Froissart et al. 2011; Bali 2013). Across a selection of available literature, the p.Leu216Leu variant has been reported in at least 55 individuals with glycogen storage disease type 1, including 47 in a homozygous state and eight in a compound heterozygous state (Kajihara et al. 1995; Akanuma et al. 2000). The p.Leu216Leu variant is reported at a frequency of 0.001271 in the East Asian population in the Exome Aggregation Consortium. The variant, although far from a splice junction, produces an aberrant transcript that eliminates 91 nucleotides and alters the reading frame, creating a premature termination at Tyr202 (Kajihara et al. 1995; Akanuma et al. 2000; Bali et al. 2013). Based on the collective evidence, the p.Leu216 variant is classified as pathogenic for glycogen storage disease type 1. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Jan 28, 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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Baylor Genetics
Accession: SCV001163788.2
First in ClinVar: Feb 28, 2020 Last updated: Mar 11, 2023 |
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Pathogenic
(Aug 11, 2024)
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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: SCV002504154.3
First in ClinVar: Apr 29, 2022 Last updated: Sep 16, 2024 |
Comment:
Reported as a common pathogenic variant in association with GSD1a among individuals of Japanese, Korean, and Chinese backgrounds (PMID: 18449899); Published functional studies demonstrate this … (more)
Reported as a common pathogenic variant in association with GSD1a among individuals of Japanese, Korean, and Chinese backgrounds (PMID: 18449899); Published functional studies demonstrate this variant results in a deletion of 91 base pairs from exon 5 (PMID: 7668282, 10748407); Also known as G727T using alternate nomenclature; This variant is associated with the following publications: (PMID: 10797430, 24980439, 31109299, 32046761, 32924126, 10748407, 33763395, 36160031, 36452356, 36595986, 36167523, 35314707, 35257483, 35783312, 18449899, 37788110, 7668282) (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: SCV002093318.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Pathogenic
(Mar 13, 2000)
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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: SCV000033023.3
First in ClinVar: Apr 04, 2013 Last updated: Jan 15, 2018 |
Comment on evidence:
In a 26-year-old man with glycogen storage disease Ia (GSD1A; 232200) and in 9 other Japanese patients from 8 unrelated families, Kajihara et al. (1995) … (more)
In a 26-year-old man with glycogen storage disease Ia (GSD1A; 232200) and in 9 other Japanese patients from 8 unrelated families, Kajihara et al. (1995) identified a splicing mutation in the G6PC gene. The first patient was the progeny of first-cousin parents and had a history of hepatomegaly and hypoglycemia since childhood. The diagnosis of GSD Ia was based on the findings of hypoglycemia, hypertriglyceridemia, hyperuricemia and liver biopsy abnormalities. Residual G6Pase activity in the liver was 18% of normal in both fresh and previously frozen liver biopsy specimens. A younger brother was also affected. The cDNA prepared from the patient's liver had a deletion of 91 nucleotides with no normal-sized cDNA. The mutation resulted in a G6Pase polypeptide 146 amino acids shorter at the carboxy-terminal portion than the normal gene product of 357 residues. It was thought that the 18% of normal activity reflected nonspecific phosphatase activity since the G6Pase activity was low or not detectable in several unrelated GSD Ia patients homozygous for this mutation. Analysis of mutant genomic DNA demonstrated a G-to-T transversion at nucleotide 727 of their G6PC sequence. Although the patient's splice site in intron 4 and exon 5 had a normal consensus sequence, normal splicing did not occur. It is thought that the single base substitution, located far from the splice junction, altered the splice site. Kajihara et al. (1995) cited data indicating that 11% of aberrant splice mutations represent the creation of new splice sites with no alteration in the authentic splice site sequences. Nakai and Sakamoto (1994) found that new 5-prime and 3-prime sites were created only in the upstream region of the authentic 5-prime and 3-prime splice sites. However, this characteristically Japanese GSD Ia mutation is an exception; a new 3-prime site occurred in the downstream region of a normal splice site. Akanuma et al. (2000) found that the most prevalent mutation in a study of 51 unrelated Japanese patients with GSD Ia was 727G-T, accounting for 88 of 102 mutant alleles. (less)
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Pathogenic
(Jan 02, 2014)
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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: SCV001132194.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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not provided
(-)
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no classification provided
Method: literature only
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Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000040461.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022
Comment:
Silent amino acid change (Leu216Leu) that creates new splice site resulting in premature termination at p.Tyr202Ter
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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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Glycogen Storage Disease Type I. | Adam MP | - | 2021 | PMID: 20301489 |
Three novel mutations of the G6PC gene identified in Chinese patients with glycogen storage disease type Ia. | Zheng BX | European journal of pediatrics | 2015 | PMID: 24980439 |
Current status of hepatic glycogen storage disease in Japan: clinical manifestations, treatments and long-term outcomes. | Kido J | Journal of human genetics | 2013 | PMID: 23486339 |
A novel type heterozygous mutation in the glucose-6-phosphatase gene in a Chinese patient with glycogen storage disease Ia. | Zhu J | Gene | 2012 | PMID: 23000067 |
Glucose-6-phosphatase deficiency. | Froissart R | Orphanet journal of rare diseases | 2011 | PMID: 21599942 |
Mutations in the glucose-6-phosphatase-alpha (G6PC) gene that cause type Ia glycogen storage disease. | Chou JY | Human mutation | 2008 | PMID: 18449899 |
Glucose-6-phosphatase gene mutations in 20 adult Japanese patients with glycogen storage disease type 1a with reference to hepatic tumors. | Nakamura T | Journal of gastroenterology and hepatology | 2001 | PMID: 11851840 |
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 |
Glucose-6-phosphatase gene (727G-->T) splicing mutation is prevalent in Hong Kong Chinese patients with glycogen storage disease type 1a. | Lam CW | Clinical genetics | 1998 | PMID: 9630072 |
Exon redefinition by a point mutation within exon 5 of the glucose-6-phosphatase gene is the major cause of glycogen storage disease type 1a in Japan. | Kajihara S | American journal of human genetics | 1995 | PMID: 7668282 |
Construction of a novel database containing aberrant splicing mutations of mammalian genes. | Nakai K | Gene | 1994 | PMID: 8163185 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=G6PC | - | - | - | - |
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Text-mined citations for rs80356484 ...
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.
NCBI staff reviewed the sequence information reported in PubMed 7668282 Fig. 2C to determine the location of this allele on the current reference sequence.