NM_000162.5(GCK):c.629T>C (p.Met210Thr) AND Maturity-onset diabetes of the young type 2

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 7, 2023
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:: RCV003117664.2

Allele description [Variation Report for NM_000162.5(GCK):c.629T>C (p.Met210Thr)]

NM_000162.5(GCK):c.629T>C (p.Met210Thr)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.629T>C (p.Met210Thr)

Other names:

NM_000162.5(GCK):c.629T>C; p.Met210Thr

HGVS:

NC_000007.14:g.44149810A>G
NG_008847.2:g.53361T>C
NM_000162.5:c.629T>CMANE SELECT
NM_001354800.1:c.629T>C
NM_033507.3:c.632T>C
NM_033508.3:c.626T>C
NP_000153.1:p.Met210Thr
NP_001341729.1:p.Met210Thr
NP_277042.1:p.Met211Thr
NP_277043.1:p.Met209Thr
LRG_1074t1:c.629T>C
LRG_1074t2:c.632T>C
LRG_1074:g.53361T>C
LRG_1074p1:p.Met210Thr
LRG_1074p2:p.Met211Thr
NC_000007.13:g.44189409A>G
NM_000162.3:c.629T>C

Protein change:

M209T

Links:

dbSNP: rs80356654

NCBI 1000 Genomes Browser:

rs80356654

Molecular consequence:

NM_000162.5:c.629T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.629T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.632T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.626T>C - 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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RNA binding protein fox-1 homolog 1 isoform 3 [Homo sapiens]
RNA binding protein fox-1 homolog 1 isoform 3 [Homo sapiens]
gi|22538409|ref|NP_665900.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003800667	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jan 7, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10525657, 9049484, 25555642, 34556497, 31956423 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003800667

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jan 7, 2023)

germline

clinical testing

PubMed (5)
[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

Citations

PubMed

Mutants of glucokinase cause hypoglycaemia- and hyperglycaemia syndromes and their analysis illuminates fundamental quantitative concepts of glucose homeostasis.

Davis EA, Cuesta-Muñoz A, Raoul M, Buettger C, Sweet I, Moates M, Magnuson MA, Matschinsky FM.

Diabetologia. 1999 Oct;42(10):1175-86.

PubMed [citation]

PMID:: 10525657

Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families.

Velho G, Blanché H, Vaxillaire M, Bellanné-Chantelot C, Pardini VC, Timsit J, Passa P, Deschamps I, Robert JJ, Weber IT, Marotta D, Pilkis SJ, Lipkind GM, Bell GI, Froguel P.

Diabetologia. 1997 Feb;40(2):217-24.

PubMed [citation]

PMID:: 9049484

See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003800667.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: GCK c.629T>C (p.Met210Thr) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251462 control chromosomes. c.629T>C has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young 2 (example, Velho_1997, Bennett_2015, Lizarzaburu-Robles_2020, Saint-Martin_2021). These data indicate that the variant is likely to be associated with disease. At-least one study reports experimental evidence demonstrating an impact on Glucokinase kinetic parameters, namely increased Km for ATP binding and decreased Kcat (approximately 12% of WT) for Glucokinase (Davies_1999). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic and one laboratory classified the variant as uncertain significance. 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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