NM_000151.4(G6PC1):c.379_380dup (p.Tyr128fs) AND Glycogen storage disease due to glucose-6-phosphatase deficiency type IA

Germline classification:: Pathogenic (11 submissions)
Last evaluated:: Mar 13, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000012777.36

Allele description [Variation Report for NM_000151.4(G6PC1):c.379_380dup (p.Tyr128fs)]

NM_000151.4(G6PC1):c.379_380dup (p.Tyr128fs)

Gene:

G6PC1:glucose-6-phosphatase catalytic subunit 1 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

17q21.31

Genomic location:

Preferred name:

NM_000151.4(G6PC1):c.379_380dup (p.Tyr128fs)

Other names:

G6PC, 2-BP INS, 459TA; 459insTA; p.Tyr128Thrfs*3

HGVS:

NC_000017.10:g.41059575_41059576insTA
NC_000017.11:g.42907559TA[3]
NG_011808.1:g.11762TA[3]
NM_000151.4:c.379_380dupMANE SELECT
NM_001270397.2:c.341-41TA[3]
NP_000142.2:p.Tyr128fs
LRG_147t1:c.379_380dup
LRG_147:g.11762TA[3]
NC_000017.10:g.41059575_41059576insTA
NC_000017.10:g.41059576TA[3]
NC_000017.10:g.41059578_41059579dupTA
NM_000151.2:c.379_380dup
NM_000151.2:c.379_380dupTA
NM_000151.3:c.379_380dup
NP_000142.1:p.Tyr128ThrfsTer3

Protein change:

Y128fs

Links:

OMIM: 613742.0001; dbSNP: rs80356488

NCBI 1000 Genomes Browser:

rs80356488

Molecular consequence:

NM_000151.4:c.379_380dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001270397.2:c.341-41TA[3] - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Glycogen storage disease due to glucose-6-phosphatase deficiency type IA (GSD1A)
Synonyms:: GSD Ia; Glycogen storage disease type 1A; Von Gierke disease; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009287; MedGen: C2919796; Orphanet: 364; Orphanet: 79258; OMIM: 232200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000033017	OMIM	no assertion criteria provided	Pathogenic (Oct 1, 1995)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 8211187, 7573034
SCV000040459	GeneReviews	no classification provided	not provided	germline	literature only
SCV000298095	National Center for Biotechnology Information, National Institutes of Health	no assertion criteria provided	Pathogenic (Aug 25, 2016)	germline	literature only	PubMed (4) [See all records that cite these PMIDs] 11386847, 11949931, 10094563, 12373566 Citation Link,
SCV000402979	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Apr 27, 2017)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 7814621, 10834516, 22899091, 19541498, 8211187, 12373566 Citation Link,
SCV000827517	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 8182131, 8211187, 22899091, 28397058, 28492532
SCV001163783	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 13, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001193974	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 13, 2019)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8211187, 22899091, 12373566, 7573034 Citation Link,
SCV001482246	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 14, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 8211187, 22899091, 28397058 Citation Link,
SCV001752573	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 30, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002023777	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 17, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002093305	Natera, Inc.	no assertion criteria provided	Pathogenic (Mar 17, 2017)	germline	clinical testing

Description

Originally appeared in GeneReview for 'Glycogen Storage Disease Type I'; deleted from update of 8/25/2016.: SCV000298095

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Molecular genetics of type 1 glycogen storage disease.

Janecke AR, Mayatepek E, Utermann G.

Mol Genet Metab. 2001 Jun;73(2):117-25. Review.

PubMed [citation]

PMID:: 11386847

Type I glycogen storage diseases: disorders of the glucose-6-phosphatase complex.

Chou JY, Matern D, Mansfield BC, Chen YT.

Curr Mol Med. 2002 Mar;2(2):121-43. Review.

PubMed [citation]

PMID:: 11949931

See all PubMed Citations (14)

Details of each submission

From OMIM, SCV000033017.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a patient with glycogen storage disease Ia (GSD1A; 232200), Lei et al. (1993) found a 2-bp insertion at nucleotide 459 (TAins459) in exon 3 of the G6PC gene. The insertion caused a frameshift with generation of a stop codon at nucleotides 467-469. The predicted gene product was a severely truncated protein of 129 amino acids. The patient was homozygous for the TA insertion and the mother, the only parent available, was heterozygous. Lei et al. (1995) referred to this mutation as 130X referring to the number of the stop codon that was generated by the frameshift. The 130X mutation had been identified only in Hispanic patients.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000040459.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From National Center for Biotechnology Information, National Institutes of Health, SCV000298095.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000402979.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The G6PC c.379_380dupTA (p.Tyr128ThrfsTer3) variant, also referred to as c.376_377insTA, causes a frameshift and is predicted to truncate the protein. The p.Tyr128ThrfsTer3 variant was first identified by Lei et al. (1993) in a homozygous state in an individual whose liver biopsy contained no detectable G6Pase activity. Since then, the variant has been identified in several affected Hispanic individuals in both the homozygous and compound heterozygous state, and is a known common variant in individuals with glycogen storage disease (GSD) type Ia, accounting for approximately 50% of disease alleles in Hispanic populations (Lei et al. 1995; Rake et al. 2000; Matern et al. 2002; Koeberl et al. 2009; Wang et al. 2013). The variant was also shown to segregate with disease (Lei et al. 1995). Control data are not reported for this variant in these studies, but the variant is reported at a frequency of 0.00115 in the Latino population of the Exome Aggregation Consortium. Transient expression analysis of the p.Tyr128ThrfsTer3 variant showed the variant abolished G6Pase activity (Rake et al. 2000). Based on the collective evidence, the p.Tyr128ThrfsTer3 variant is classified as pathogenic for glycogen storage disease type I. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000827517.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Tyr128Thrfs*3) in the G6PC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in G6PC are known to be pathogenic (PMID: 8182131). This variant is present in population databases (rs756356652, gnomAD 0.07%). This premature translational stop signal has been observed in individuals with glycogen storage disease type Ia (PMID: 8211187, 22899091, 28397058). ClinVar contains an entry for this variant (Variation ID: 11997). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001163783.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV001193974.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

NM_000151.3(G6PC):c.379_380dupTA(Y128Tfs*3) is classified as pathogenic in the context of glycogen storage disease type Ia. Sources cited for classification include the following: PMID 8211187, 22899091, 12373566 and 7573034. Classification of NM_000151.3(G6PC):c.379_380dupTA(Y128Tfs*3) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001482246.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: G6PC c.379_380dupTA (p.Tyr128ThrfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00011 in 251208 control chromosomes. c.379_380dupTA has been reported in the literature in multiple individuals affected with Glycogen Storage Disease Type Ia (example, Lei_1993, Wang_2013, Peeks_2017). 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 (Lei_1993). The most pronounced variant effect results in no detectable G6Pase activity in liver biopsy specimens from an affected patient. Seven 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. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV001752573.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002023777.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002093305.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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