NM_000162.5(GCK):c.731T>G (p.Val244Gly) AND Maturity onset diabetes mellitus in young

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 22, 2019
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:: RCV002380111.2

Allele description [Variation Report for NM_000162.5(GCK):c.731T>G (p.Val244Gly)]

NM_000162.5(GCK):c.731T>G (p.Val244Gly)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.731T>G (p.Val244Gly)

HGVS:

NC_000007.14:g.44147782A>C
NG_008847.2:g.55389T>G
NM_000162.5:c.731T>GMANE SELECT
NM_001354800.1:c.731T>G
NM_033507.3:c.734T>G
NM_033508.3:c.728T>G
NP_000153.1:p.Val244Gly
NP_001341729.1:p.Val244Gly
NP_277042.1:p.Val245Gly
NP_277043.1:p.Val243Gly
LRG_1074t1:c.731T>G
LRG_1074t2:c.734T>G
LRG_1074:g.55389T>G
LRG_1074p1:p.Val244Gly
LRG_1074p2:p.Val245Gly
NC_000007.13:g.44187381A>C
NM_000162.3:c.731T>G

Protein change:

V243G

Molecular consequence:

NM_000162.5:c.731T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.731T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.734T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.728T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Maturity onset diabetes mellitus in young (MODY)
Synonyms:: Mason type diabetes
Identifiers:: MONDO: MONDO:0018911; MedGen: C0342276; Orphanet: 552; OMIM: 606391; Human Phenotype Ontology: HP:0004904

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002674396	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Mar 22, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19358091, 22493702, 24735133 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002674396

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Mar 22, 2019)

germline

clinical testing

PubMed (3)
[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

Glucokinase gene mutation screening in Argentinean clinically characterized MODY patients.

Lopez AP, Foscaldi SA, Pérez MS, Krochik G, Rodríguez M, Traversa M, Puchulu FM, Hirschler V, Bergada I, Frechtel GD.

Exp Clin Endocrinol Diabetes. 2009 Sep;117(8):391-4. doi: 10.1055/s-0029-1214427. Epub 2009 Apr 8.

PubMed [citation]

PMID:: 19358091

Identification and functional characterisation of novel glucokinase mutations causing maturity-onset diabetes of the young in Slovakia.

Valentínová L, Beer NL, Staník J, Tribble ND, van de Bunt M, Hučková M, Barrett A, Klimeš I, Gašperíková D, Gloyn AL.

PLoS One. 2012;7(4):e34541. doi: 10.1371/journal.pone.0034541. Epub 2012 Apr 6.

PubMed [citation]

PMID:: 22493702
PMCID:: PMC3321013

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002674396.2

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

Description

The p.V244G variant (also known as c.731T>G), located in coding exon 7 of the GCK gene, results from a T to G substitution at nucleotide position 731. The valine at codon 244 is replaced by glycine, an amino acid with dissimilar properties. This alteration was reported in two proband's with a clinical history consistent with GCK-MODY and was shown to segregate with disease in each of their families (Valentínová L et al. PLoS ONE, 2012 Apr;7:e34541). Functional studies evaluating enzyme kinetics using recombinant protein showed V244G to be kinetically inactivating as compared to wild-type (Valentínová L et al. PLoS ONE, 2012 Apr;7:e34541). In addition, another disease-causing alteration at the same codon, c.731T>A (p.V244E), has previously been reported (Lopez AP et al. Exp. Clin. Endocrinol. Diabetes, 2009 Sep;117:391-4; Costantini S et al. Clin. Genet., 2015 May;87:440-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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: May 1, 2024

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