NM_000151.4(G6PC1):c.809G>T (p.Gly270Val) AND Glycogen storage disease due to glucose-6-phosphatase deficiency type IA

Germline classification:: Pathogenic/Likely pathogenic (9 submissions)
Last evaluated:: Apr 18, 2023
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:: RCV000239699.22

Allele description [Variation Report for NM_000151.4(G6PC1):c.809G>T (p.Gly270Val)]

NM_000151.4(G6PC1):c.809G>T (p.Gly270Val)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.31

Genomic location:

Preferred name:

NM_000151.4(G6PC1):c.809G>T (p.Gly270Val)

HGVS:

NC_000017.11:g.42911161G>T
NG_011808.1:g.15364G>T
NM_000151.4:c.809G>TMANE SELECT
NM_001270397.2:c.*201G>T
NP_000142.2:p.Gly270Val
LRG_147t1:c.809G>T
LRG_147:g.15364G>T
LRG_147p1:p.Gly270Val
NC_000017.10:g.41063178G>T
NM_000151.2:c.809G>T
NM_000151.3:c.809G>T
NP_000142.1:p.Gly270Val
P35575:p.Gly270Val

Protein change:

G270V

Links:

UniProtKB: P35575#VAR_005250; dbSNP: rs80356483

NCBI 1000 Genomes Browser:

rs80356483

Molecular consequence:

NM_001270397.2:c.*201G>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000151.4:c.809G>T - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000298096	National Center for Biotechnology Information, National Institutes of Health	no assertion criteria provided	Pathogenic (Aug 25, 2016)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 11386847, 11949931 Citation Link,
SCV000486040	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Mar 18, 2016)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11739393, 7573034, 10234610, 25308557, 10094563, 8733042, 23352793 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000492901	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 20, 2015)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000829977	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 18, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 7573034, 8733042, 10234610, 28397058, 28659124, 28492532
SCV001163790	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001478597	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 18, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7573034, 8733042, 28659124, 10234610, 28397058 Citation Link,
SCV002023773	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 10, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002093325	Natera, Inc.	no assertion criteria provided	Pathogenic (Mar 17, 2017)	germline	clinical testing
SCV002779285	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 21, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Description

Originally appeared in GeneReview for 'Glycogen Storage Disease Type I'; deleted from update of 8/25/2016.: SCV000298096

Help

Summary from all submissions

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

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 (13)

Details of each submission

From National Center for Biotechnology Information, National Institutes of Health, SCV000298096.1

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

#	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 Counsyl, SCV000486040.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

#	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 Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV000492901.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000829977.7

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

Description

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).

#	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, SCV001163790.1

#	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	germline	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, SCV001478597.1

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

Description

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.

#	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 Revvity Omics, Revvity, SCV002023773.3

#	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., SCV002093325.1

#	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

From Fulgent Genetics, Fulgent Genetics, SCV002779285.1

#	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

Last Updated: Sep 29, 2024

Relating variation to medicine