NM_000151.4(G6PC1):c.189G>A (p.Trp63Ter) AND Glycogen storage disease due to glucose-6-phosphatase deficiency type IA

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 29, 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:: RCV000169341.13

Allele description [Variation Report for NM_000151.4(G6PC1):c.189G>A (p.Trp63Ter)]

NM_000151.4(G6PC1):c.189G>A (p.Trp63Ter)

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.189G>A (p.Trp63Ter)

HGVS:

NC_000017.11:g.42901065G>A
NG_011808.1:g.5268G>A
NM_000151.4:c.189G>AMANE SELECT
NM_001270397.2:c.189G>A
NP_000142.2:p.Trp63Ter
NP_001257326.1:p.Trp63Ter
LRG_147:g.5268G>A
NC_000017.10:g.41053082G>A
NM_000151.3:c.189G>A

Protein change:

W63*

Links:

dbSNP: rs764920787

NCBI 1000 Genomes Browser:

rs764920787

Molecular consequence:

NM_000151.4:c.189G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001270397.2:c.189G>A - nonsense - [Sequence Ontology: SO:0001587]

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

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C-type lectin domain family 10 member A isoform 2 [Homo sapiens]
C-type lectin domain family 10 member A isoform 2 [Homo sapiens]
gi|53832016|ref|NP_006335.2|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000220703	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Sep 17, 2014)	unknown	literature only	PubMed (6) [See all records that cite these PMIDs] 10094563, 7573034, 10834516, 12373566, 23352793, 11949931 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV001220526	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8182131, 7573034, 11949931, 28492532
SCV002093293	Natera, Inc.	no assertion criteria provided	Pathogenic (Mar 17, 2017)	germline	clinical testing
SCV002819522	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 14, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 7573034, 10834516, 34258141, 10094563 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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

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

Rapid screening of 12 common mutations in Turkish GSD 1a patients using electronic DNA microarray.

Eminoglu TF, Ezgu FS, Hasanoglu A, Tumer L.

Gene. 2013 Apr 15;518(2):346-50. doi: 10.1016/j.gene.2012.12.104. Epub 2013 Jan 23.

PubMed [citation]

PMID:: 23352793

See all PubMed Citations (9)

Details of each submission

From Counsyl, SCV000220703.2

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

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001220526.5

#	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 creates a premature translational stop signal (p.Trp63*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with glycogen storage disease (PMID: 7573034, 11949931). ClinVar contains an entry for this variant (Variation ID: 188966). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 Natera, Inc., SCV002093293.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002819522.1

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

Description

Variant summary: G6PC c.189G>A (p.Trp63X), also referred to as c.268G>A, 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 4e-06 in 251420 control chromosomes (gnomAD). c.189G>A has been reported in the literature in individuals affected with Glycogen Storage Disease Type Ia (e.g. Lei_1995, Rake_1999, Rake_2000). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant results in little to no protein expression, approximately 2% of the WT protein (Plona_2021). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both 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

Last Updated: Sep 29, 2024

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