NM_000162.5(GCK):c.704T>C (p.Met235Thr) AND not provided

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 11, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003556090.3

Allele description [Variation Report for NM_000162.5(GCK):c.704T>C (p.Met235Thr)]

NM_000162.5(GCK):c.704T>C (p.Met235Thr)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.704T>C (p.Met235Thr)

HGVS:

NC_000007.14:g.44147809A>G
NG_008847.2:g.55362T>C
NM_000162.5:c.704T>CMANE SELECT
NM_001354800.1:c.704T>C
NM_033507.3:c.707T>C
NM_033508.3:c.701T>C
NP_000153.1:p.Met235Thr
NP_001341729.1:p.Met235Thr
NP_277042.1:p.Met236Thr
NP_277043.1:p.Met234Thr
LRG_1074t1:c.704T>C
LRG_1074t2:c.707T>C
LRG_1074:g.55362T>C
LRG_1074p1:p.Met235Thr
LRG_1074p2:p.Met236Thr
NC_000007.13:g.44187408A>G
NM_000162.3:c.704T>C

Protein change:

M234T

Links:

dbSNP: rs193922323

NCBI 1000 Genomes Browser:

rs193922323

Molecular consequence:

NM_000162.5:c.704T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.704T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.707T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.701T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004295165	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 11, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 14517946, 17186219, 24323243, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004295165

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 11, 2024)

germline

clinical testing

PubMed (4)
[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

Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy.

Gloyn AL.

Hum Mutat. 2003 Nov;22(5):353-62. Review.

PubMed [citation]

PMID:: 14517946

Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity.

García-Herrero CM, Galán M, Vincent O, Flández B, Gargallo M, Delgado-Alvarez E, Blázquez E, Navas MA.

Diabetologia. 2007 Feb;50(2):325-33. Epub 2006 Dec 21.

PubMed [citation]

PMID:: 17186219

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004295165.2

#	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 replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 235 of the GCK protein (p.Met235Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 14517946). ClinVar contains an entry for this variant (Variation ID: 36248). 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 GCK protein function with a negative predictive value of 80%. This variant disrupts the p.Met235 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17186219, 24323243). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

Last Updated: Jun 8, 2025

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