NM_000162.5(GCK):c.718A>G (p.Asn240Asp) AND Maturity-onset diabetes of the young type 2

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 8, 2017
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:: RCV000754808.2

Allele description [Variation Report for NM_000162.5(GCK):c.718A>G (p.Asn240Asp)]

NM_000162.5(GCK):c.718A>G (p.Asn240Asp)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.718A>G (p.Asn240Asp)

HGVS:

NC_000007.14:g.44147795T>C
NG_008847.2:g.55376A>G
NM_000162.5:c.718A>GMANE SELECT
NM_001354800.1:c.718A>G
NM_033507.3:c.721A>G
NM_033508.3:c.715A>G
NP_000153.1:p.Asn240Asp
NP_001341729.1:p.Asn240Asp
NP_277042.1:p.Asn241Asp
NP_277043.1:p.Asn239Asp
LRG_1074t1:c.718A>G
LRG_1074t2:c.721A>G
LRG_1074:g.55376A>G
LRG_1074p1:p.Asn240Asp
LRG_1074p2:p.Asn241Asp
NC_000007.13:g.44187394T>C
NM_000162.3:c.718A>G

Protein change:

N239D

Links:

dbSNP: rs1562715574

NCBI 1000 Genomes Browser:

rs1562715574

Molecular consequence:

NM_000162.5:c.718A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.718A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.721A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.715A>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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LOC4344175 [Oryza sativa Japonica Group]
LOC4344175 [Oryza sativa Japonica Group]
Gene ID:4344175

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000882457	Translational Genomics Laboratory, University of Maryland School of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 8, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24735133, 18382660, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000882457

Translational Genomics Laboratory, University of Maryland School of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 8, 2017)

germline

clinical testing

PubMed (3)
[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

Genetic and bioinformatics analysis of four novel GCK missense variants detected in Caucasian families with GCK-MODY phenotype.

Costantini S, Malerba G, Contreas G, Corradi M, Marin Vargas SP, Giorgetti A, Maffeis C.

Clin Genet. 2015 May;87(5):440-7. doi: 10.1111/cge.12406. Epub 2014 Jun 6.

PubMed [citation]

PMID:: 24735133

Glucokinase gene mutations: structural and genotype-phenotype analyses in MODY children from South Italy.

Tinto N, Zagari A, Capuano M, De Simone A, Capobianco V, Daniele G, Giugliano M, Spadaro R, Franzese A, Sacchetti L.

PLoS One. 2008 Apr 2;3(4):e1870. doi: 10.1371/journal.pone.0001870.

PubMed [citation]

PMID:: 18382660
PMCID:: PMC2270336

See all PubMed Citations (3)

Details of each submission

From Translational Genomics Laboratory, University of Maryland School of Medicine, SCV000882457.1

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

Description

The c.718A>G variant in codon 240 (exon 7) of the glucokinase gene, GCK, results in the substitution of Asparagine to Aspartic Acid. The c.718A>G was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, this variant has been reported to segregate with diabetes in a family (father and two sons) with a clinical picture consistent with Maturity-Onset Diabetes of the Young, Type 2 (MODY2, also called GCK-MODY) (24735133). This residue is important for H-bonding within the protein and alteration is predicted to disrupt the tertiary structure of the protein (24735133;18382660). Additionally, multiple lines of computational evidence (LRT, MutationTaster, FATHMM, MetaSVM, MetaLR, CADD, GERP, PROVEAN) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. In addition, the personal and family history for this case is highly suggestive of GCK-MODY.ACMG criteria = PM1, PM2, PP1, PP3

#	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: Jun 23, 2024

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