NM_000151.4(G6PC1):c.161A>C (p.Gln54Pro) AND Glycogen storage disease due to glucose-6-phosphatase deficiency type IA

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Nov 11, 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:: RCV000411603.11

Allele description [Variation Report for NM_000151.4(G6PC1):c.161A>C (p.Gln54Pro)]

NM_000151.4(G6PC1):c.161A>C (p.Gln54Pro)

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.161A>C (p.Gln54Pro)

HGVS:

NC_000017.11:g.42901037A>C
NG_011808.1:g.5240A>C
NM_000151.4:c.161A>CMANE SELECT
NM_001270397.2:c.161A>C
NP_000142.2:p.Gln54Pro
NP_001257326.1:p.Gln54Pro
LRG_147:g.5240A>C
NC_000017.10:g.41053054A>C
NM_000151.3:c.161A>C

Protein change:

Q54P

Links:

dbSNP: rs1057517008

NCBI 1000 Genomes Browser:

rs1057517008

Molecular consequence:

NM_000151.4:c.161A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001270397.2:c.161A>C - 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
SCV000486578	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jun 27, 2016)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11739393, 11058903, 15542400, 10447271 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000931561	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 11, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10447271, 15542400, 11739393, 28492532
SCV001362493	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 7, 2019)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 12373566, 11739393, 15542400, 11058903, 11949931, 18449899, 10834516, 10447271 Citation Link,
SCV002093292	Natera, Inc.	no assertion criteria provided	Pathogenic (Mar 17, 2017)	germline	clinical testing

Help

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
not provided	unknown	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):240-242.

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 (9)

Details of each submission

From Counsyl, SCV000486578.2

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

#	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 Invitae, SCV000931561.4

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

Description

This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 54 of the G6PC protein (p.Gln54Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with glycogen storage disease type 1a (PMID: 10447271, 15542400). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 371101). 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 80%. Experimental studies have shown that this missense change affects G6PC function (PMID: 11739393). 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362493.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Variant summary: G6PC c.161A>C (p.Gln54Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251444 control chromosomes (gnomAD). The variant, c.161A>C, has been reported in the literature in multiple individuals affected with Glycogen Storage Disease Type Ia (Trioche_1999, Angaroni_2004). These data indicate that the variant is very likely to be associated with disease. One publication, Shieh_2002, reports G6Pase activity of this residual variant remained <10% of normal activity. One ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites 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

From Natera, Inc., SCV002093292.1

#	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: Feb 20, 2024

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