NM_000162.5(GCK):c.751A>G (p.Met251Val) AND Maturity-onset diabetes of the young type 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 22, 2022
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:: RCV002225198.2

Allele description [Variation Report for NM_000162.5(GCK):c.751A>G (p.Met251Val)]

NM_000162.5(GCK):c.751A>G (p.Met251Val)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.751A>G (p.Met251Val)

HGVS:

NC_000007.14:g.44147762T>C
NG_008847.2:g.55409A>G
NM_000162.5:c.751A>GMANE SELECT
NM_001354800.1:c.751A>G
NM_033507.3:c.754A>G
NM_033508.3:c.748A>G
NP_000153.1:p.Met251Val
NP_001341729.1:p.Met251Val
NP_277042.1:p.Met252Val
NP_277043.1:p.Met250Val
LRG_1074t1:c.751A>G
LRG_1074t2:c.754A>G
LRG_1074:g.55409A>G
LRG_1074p1:p.Met251Val
LRG_1074p2:p.Met252Val
NC_000007.13:g.44187361T>C

Protein change:

M250V

Links:

dbSNP: rs2128820620

NCBI 1000 Genomes Browser:

rs2128820620

Molecular consequence:

NM_000162.5:c.751A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.751A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.754A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.748A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Maturity-onset diabetes of the young type 2
Synonyms:: MODY type 2; Diabetes mellitus MODY type 2; MODY glucokinase-related; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007453; MedGen: C0342277; Orphanet: 552; OMIM: 125851

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tubulin monoglutamylase TTLL4 [Homo sapiens]
tubulin monoglutamylase TTLL4 [Homo sapiens]
gi|217330594|ref|NP_055455.3|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002503751	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 22, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 14517946, 20337973, 24804978, 29792621, 29927023, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002503751

Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 22, 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	yes	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

Glucokinase diabetes in 103 families from a country-based study in the Czech Republic: geographically restricted distribution of two prevalent GCK mutations.

Pruhova S, Dusatkova P, Sumnik Z, Kolouskova S, Pedersen O, Hansen T, Cinek O, Lebl J.

Pediatr Diabetes. 2010 Dec;11(8):529-35. doi: 10.1111/j.1399-5448.2010.00646.x.

PubMed [citation]

PMID:: 20337973

See all PubMed Citations (6)

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV002503751.2

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

Description

This sequence change is predicted to replace methionine with valine at codon 251 of the GCK protein, p.(Met251Val). The methionine residue is highly conserved (100 vertebrates, UCSC), and is located in the hexokinase 2 domain. There is a small physicochemical difference between methionine and valine. The variant is absent in a large population cohort (gnomAD v2.1), and has been identified in at least four cases with a clinical diagnosis of maturity-onset diabetes of the young (MODY), co-segregating with diabetes in at least two families (PMID: 20337973, 24804978, 29927023; https://doi.org/10.1093/edrv/36.supp.1). Furthermore, the cases with the variant demonstrate the stable fasting hyperglycaemia, characteristic of MODY type 2 (PMID: 24804978, 29792621). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Additionally, a different missense involving this amino acid residue (p.Met251Ile) has been determined to be likely pathogenic (PMID: 14517946). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PM2, PM5, PP1, PP3, PP4.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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