NM_000151.4(G6PC1):c.202G>A (p.Gly68Arg) AND Glycogen storage disease due to glucose-6-phosphatase deficiency type IA

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Sep 1, 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:: RCV002237083.7

Allele description [Variation Report for NM_000151.4(G6PC1):c.202G>A (p.Gly68Arg)]

NM_000151.4(G6PC1):c.202G>A (p.Gly68Arg)

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.202G>A (p.Gly68Arg)

HGVS:

NC_000017.11:g.42901078G>A
NG_011808.1:g.5281G>A
NM_000151.3:c.202G>A
NM_000151.4:c.202G>AMANE SELECT
NM_001270397.2:c.202G>A
NP_000142.2:p.Gly68Arg
NP_001257326.1:p.Gly68Arg
LRG_147:g.5281G>A
NC_000017.10:g.41053095G>A

Protein change:

G68R

Links:

dbSNP: rs1567702819

NCBI 1000 Genomes Browser:

rs1567702819

Molecular consequence:

NM_000151.4:c.202G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001270397.2:c.202G>A - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002510569	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 19, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9700613, 11310582, 33258288, 11739393, 28492532
SCV004100199	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 1, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12373566, 11739393, 11310582, 31508908, 33258288, 9700613 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002510569

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 19, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004100199

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Sep 1, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Glycogen storage disease type I: diagnosis and phenotype/genotype correlation.

Matern D, Seydewitz HH, Bali D, Lang C, Chen YT.

Eur J Pediatr. 2002 Oct;161 Suppl 1:S10-9. Epub 2002 Jul 27.

PubMed [citation]

PMID:: 12373566

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002510569.3

#	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 replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 68 of the G6PC protein (p.Gly68Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with glycogen storage disease (PMID: 9700613, 11310582, 33258288). ClinVar contains an entry for this variant (Variation ID: 1682484). 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. Experimental studies have shown that this missense change affects G6PC function (PMID: 11739393). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004100199.1

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

Description

Variant summary: G6PC1 c.202G>A (p.Gly68Arg) results in a non-conservative amino acid change located in the phosphatidic acid phosphatase 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 251406 control chromosomes (gnomAD). c.202G>A has been reported in the literature as a biallelic genotype in individuals affected with Glycogen Storage Disease Type Ia, most of whom were of Brazilian ancestry (e.g. Sartorato_1998, Reis_2001, Matern_2002, Sperb-Ludwig_2019, Quaio_2020). These data indicate that the variant is likely to be associated with disease. A functional study evaluating an impact of the variant in vitro found that it had <10% enzymatic activity compared to the WT (Shieh_2002). The following publications have been ascertained in the context of this evaluation (PMID: 12373566, 33258288, 11310582, 9700613, 31508908, 11739393). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as likely 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

Last Updated: Sep 29, 2024

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