NM_000151.4(G6PC1):c.910G>A (p.Val304Ile) AND Glycogen storage disease due to glucose-6-phosphatase deficiency type IA

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Aug 8, 2022
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:: RCV001240860.7

Allele description [Variation Report for NM_000151.4(G6PC1):c.910G>A (p.Val304Ile)]

NM_000151.4(G6PC1):c.910G>A (p.Val304Ile)

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.910G>A (p.Val304Ile)

Other names:

p.V304I:GTC>ATC

HGVS:

NC_000017.11:g.42911262G>A
NG_011808.1:g.15465G>A
NM_000151.4:c.910G>AMANE SELECT
NM_001270397.2:c.*302G>A
NP_000142.2:p.Val304Ile
LRG_147t1:c.910G>A
LRG_147:g.15465G>A
NC_000017.10:g.41063279G>A
NM_000151.2:c.910G>A
NM_000151.3:c.910G>A

Protein change:

V304I

Links:

dbSNP: rs768385469

NCBI 1000 Genomes Browser:

rs768385469

Molecular consequence:

NM_001270397.2:c.*302G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000151.4:c.910G>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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MIMAG Metagenome-assembled Genome sample from Empedobacter falsenii
MIMAG Metagenome-assembled Genome sample from Empedobacter falsenii

biosample
membrane, 0min, replicate2
membrane, 0min, replicate2

biosample
wu:fb95b07 wu:fb95b07 [Danio rerio]
wu:fb95b07 wu:fb95b07 [Danio rerio]
Gene ID:323318

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001413837	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 8, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34258141, 28492532
SCV002093327	Natera, Inc.	no assertion criteria provided	Uncertain significance (May 3, 2018)	germline	clinical testing
SCV002783094	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 20, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001413837

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 8, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002093327

Natera, Inc.

no assertion criteria provided

Uncertain significance
(May 3, 2018)

germline

clinical testing

SCV002783094

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 20, 2022)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

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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	clinical testing

Citations

PubMed

Classifying molecular phenotypes of G6PC variants for pathogenic properties and to guide therapeutic development.

Plona KL, Eastman JF, Drumm ML.

JIMD Rep. 2021 Jul;60(1):56-66. doi: 10.1002/jmd2.12215.

PubMed [citation]

PMID:: 34258141
PMCID:: PMC8260485

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

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001413837.3

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

Description

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 304 of the G6PC protein (p.Val304Ile). This variant is present in population databases (rs768385469, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with G6PC-related conditions. ClinVar contains an entry for this variant (Variation ID: 214463). 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 not expected to disrupt G6PC protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on G6PC function (PMID: 34258141). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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., SCV002093327.1

#	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, SCV002783094.1

#	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

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