NM_000162.5(GCK):c.682A>G (p.Thr228Ala) AND not provided

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Mar 4, 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:: RCV000516688.5

Allele description [Variation Report for NM_000162.5(GCK):c.682A>G (p.Thr228Ala)]

NM_000162.5(GCK):c.682A>G (p.Thr228Ala)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.682A>G (p.Thr228Ala)

Other names:

NM_000162.5(GCK):c.682A>G

HGVS:

NC_000007.14:g.44147831T>C
NG_008847.2:g.55340A>G
NM_000162.5:c.682A>GMANE SELECT
NM_001354800.1:c.682A>G
NM_033507.3:c.685A>G
NM_033508.3:c.679A>G
NP_000153.1:p.Thr228Ala
NP_001341729.1:p.Thr228Ala
NP_277042.1:p.Thr229Ala
NP_277043.1:p.Thr227Ala
LRG_1074t1:c.682A>G
LRG_1074t2:c.685A>G
LRG_1074:g.55340A>G
LRG_1074p1:p.Thr228Ala
LRG_1074p2:p.Thr229Ala
NC_000007.13:g.44187430T>C
NC_000007.13:g.44187430T>C
NM_000162.3:c.682A>G
NM_000162.4(GCK):c.682A>G
p.THR228ALA
p.Thr228Ala

Protein change:

T227A

Links:

dbSNP: rs1332966015

NCBI 1000 Genomes Browser:

rs1332966015

Molecular consequence:

NM_000162.5:c.682A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.682A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.685A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.679A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Calocera viscosa TUFC12733
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000613450	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Likely pathogenic (Nov 3, 2017)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 12955723, 15752705, 20458967, 19551638, 19790256, 22389783, 15102714, 18056790, 26467025
SCV003440138	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 4, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12955723, 22335469, 24323243, 31638168, 15752705, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000613450

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Likely pathogenic
(Nov 3, 2017)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV003440138

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 4, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

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

Citations

PubMed

Characterization of glucokinase polymorphisms associated with maturity-onset diabetes of the young (MODY2) in Jordanian population.

Al-Sheyab F, Khamaiseh E, Halaweh MA, Khaul RW.

Tsitol Genet. 2009 Sep-Oct;43(5):58-63.

PubMed [citation]

PMID:: 20458967

Screening of mutations in the GCK gene in Jordanian maturity-onset diabetes of the young type 2 (MODY2) patients.

Khalil R, Al-Sheyab F, Khamaiseh E, Halaweh MA, Abder-Rahman HA.

Genet Mol Res. 2009 May 5;8(2):500-6.

PubMed [citation]

PMID:: 19551638

See all PubMed Citations (13)

Details of each submission

From Athena Diagnostics, SCV000613450.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003440138.2

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

Description

This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 228 of the GCK protein (p.Thr228Ala). This missense change has been observed in individuals with clinical features of autosomal dominant GCK-related conditions (PMID: 12955723, 31638168; Invitae). 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.Thr228 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22335469, 24323243, 31638168). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GCK function (PMID: 15752705). 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: "Benign"; Align-GVGD: "Class C55"). ClinVar contains an entry for this variant (Variation ID: 447413).

#	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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