NM_000151.4(G6PC1):c.764C>T (p.Thr255Ile) AND Glycogen storage disease due to glucose-6-phosphatase deficiency type IA

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Aug 3, 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:: RCV001810537.10

Allele description [Variation Report for NM_000151.4(G6PC1):c.764C>T (p.Thr255Ile)]

NM_000151.4(G6PC1):c.764C>T (p.Thr255Ile)

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.764C>T (p.Thr255Ile)

HGVS:

NC_000017.11:g.42911116C>T
NG_011808.1:g.15319C>T
NM_000151.4:c.764C>TMANE SELECT
NM_001270397.2:c.*156C>T
NP_000142.2:p.Thr255Ile
LRG_147:g.15319C>T
NC_000017.10:g.41063133C>T
NM_000151.3:c.764C>T

Protein change:

T255I

Links:

dbSNP: rs2056092654

NCBI 1000 Genomes Browser:

rs2056092654

Molecular consequence:

NM_001270397.2:c.*156C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000151.4:c.764C>T - 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
SCV002060020	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Likely pathogenic (Nov 8, 2021)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15151508, 11739393, 31415093 Citation Link,
SCV002510558	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 8, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 32046761, 11739393, 15151508, 28492532
SCV002572275	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Aug 3, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11739393, 11949931, 31415093, 15151508 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002060020

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))

Likely pathogenic
(Nov 8, 2021)

unknown

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV002510558

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 8, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002572275

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Aug 3, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

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

Predominance of the c.648G > T G6PC gene mutation and late complications in Korean patients with glycogen storage disease type Ia.

Kim YM, Choi JH, Lee BH, Kim GH, Kim KM, Yoo HW.

Orphanet J Rare Dis. 2020 Feb 11;15(1):45. doi: 10.1186/s13023-020-1321-0.

PubMed [citation]

PMID:: 32046761
PMCID:: PMC7014716

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 (6)

Details of each submission

From Myriad Genetics, Inc., SCV002060020.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

NM_000151.3(G6PC1):c.764C>T(T255I) is a missense variant classified as likely pathogenic in the context of glycogen storage disease type Ia. T255I has been observed in cases with relevant disease (PMID: 11739393, 15151508, 31415093). Functional assessments of this variant are available in the literature (PMID: 11739393). T255I has not been observed in population frequency databases. In summary, NM_000151.3(G6PC1):c.764C>T(T255I) is a missense variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

#	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, SCV002510558.3

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

Description

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. This variant disrupts the p.Thr255 amino acid residue in G6PC. Other variant(s) that disrupt this residue have been observed in individuals with G6PC-related conditions (PMID: 11739393, 15151508, 32046761), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this variant affects G6PC function (PMID: 11739393). 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. This variant has been observed in individuals with glycogen storage disease (PMID: 11739393, 15151508). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 255 of the G6PC protein (p.Thr255Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine.

#	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, SCV002572275.1

#	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.764C>T (p.Thr255Ile) results in a non-conservative amino acid change in 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 251378 control chromosomes. c.764C>T has been reported in the literature in individuals affected with Glycogen Storage Disease Type Ia (Shieh_2002, Chou_2002, Dahlberg_2020, Ki_2004). These data indicate that the variant is likely to be associated with disease. The variant was reported to have reduced phosphohydrolase activity (Shieh_2002). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was 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

Last Updated: Sep 29, 2024

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