NM_000151.4(G6PC1):c.326G>A (p.Cys109Tyr) AND Glycogen storage disease due to glucose-6-phosphatase deficiency type IA

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Sep 18, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000270253.3

Allele description [Variation Report for NM_000151.4(G6PC1):c.326G>A (p.Cys109Tyr)]

NM_000151.4(G6PC1):c.326G>A (p.Cys109Tyr)

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.326G>A (p.Cys109Tyr)
HGVS:
  • NC_000017.11:g.42904026G>A
  • NG_011808.1:g.8229G>A
  • NM_000151.4:c.326G>AMANE SELECT
  • NM_001270397.2:c.326G>A
  • NP_000142.2:p.Cys109Tyr
  • NP_001257326.1:p.Cys109Tyr
  • LRG_147t1:c.326G>A
  • LRG_147:g.8229G>A
  • NC_000017.10:g.41056043G>A
  • NM_000151.2:c.326G>A
  • NM_000151.3:c.326G>A
Protein change:
C109Y
Links:
dbSNP: rs886052955
NCBI 1000 Genomes Browser:
rs886052955
Molecular consequence:
  • NM_000151.4:c.326G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270397.2:c.326G>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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000402977Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Jan 13, 2018)
germlineclinical testing

Citation Link,

SCV001381721Invitaecriteria provided, single submitter
Likely pathogenic
(Sep 18, 2019)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Long-read sequencing identified a causal structural variant in an exome-negative case and enabled preimplantation genetic diagnosis.

Miao H, Zhou J, Yang Q, Liang F, Wang D, Ma N, Gao B, Du J, Lin G, Wang K, Zhang Q.

Hereditas. 2018;155:32. doi: 10.1186/s41065-018-0069-1.

PubMed [citation]
PMID:
30279644
PMCID:
PMC6162922

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

Details of each submission

From Illumina Clinical Services Laboratory,Illumina, SCV000402977.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001381721.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces cysteine with tyrosine at codon 109 of the G6PC protein (p.Cys109Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with glycogen storage disease (PMID: 30279644, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 323360). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 7, 2021

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