NM_000162.5(GCK):c.748C>T (p.Arg250Cys) AND Maturity onset diabetes mellitus in young

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Nov 6, 2020
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV002393068.4

Allele description [Variation Report for NM_000162.5(GCK):c.748C>T (p.Arg250Cys)]

NM_000162.5(GCK):c.748C>T (p.Arg250Cys)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.748C>T (p.Arg250Cys)

Other names:

NM_000162.5(GCK):c.748C>T

HGVS:

NC_000007.14:g.44147765G>A
NG_008847.2:g.55406C>T
NM_000162.5:c.748C>TMANE SELECT
NM_001354800.1:c.748C>T
NM_033507.3:c.751C>T
NM_033508.3:c.745C>T
NP_000153.1:p.Arg250Cys
NP_001341729.1:p.Arg250Cys
NP_277042.1:p.Arg251Cys
NP_277043.1:p.Arg249Cys
LRG_1074t1:c.748C>T
LRG_1074t2:c.751C>T
LRG_1074:g.55406C>T
LRG_1074p1:p.Arg250Cys
LRG_1074p2:p.Arg251Cys
NC_000007.13:g.44187364G>A
NC_000007.13:g.44187364G>A
NM_000162.3(GCK):c.748C>T
NM_000162.3:c.748C>T
p.ARG250CYS
p.Arg250Cys

Protein change:

R249C

Links:

dbSNP: rs1057524904

NCBI 1000 Genomes Browser:

rs1057524904

Molecular consequence:

NM_000162.5:c.748C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.748C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.751C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.745C>T - 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
SCV002668912	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jul 7, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17204055, 19790256 Citation Link,
SCV004848482	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Nov 6, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 19790256, 19069349, 30245511, 17204055, 20337973, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002668912

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jul 7, 2018)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV004848482

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Nov 6, 2020)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia.

Osbak KK, Colclough K, Saint-Martin C, Beer NL, Bellanné-Chantelot C, Ellard S, Gloyn AL.

Hum Mutat. 2009 Nov;30(11):1512-26. doi: 10.1002/humu.21110. Review.

PubMed [citation]

PMID:: 19790256

[Novel glucokinase mutation in a boy with maturity-onset diabetes of the young].

Milenković T, Zdravković D, Mitrović K.

Srp Arh Celok Lek. 2008 Sep-Oct;136(9-10):542-4. Serbian.

PubMed [citation]

PMID:: 19069349

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV002668912.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.R250C variant (also known as c.748C>T), located in coding exon 7 of the GCK gene, results from a C to T substitution at nucleotide position 748. The arginine at codon 250 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was first reported in a Czech individual with a clinical diagnosis of MODY and was subsequently reported in three additional MODY families (Pinterova D et al. Clin. Genet., 2007 Jan;71:95-6; Osbak KK et al. Hum. Mutat., 2009 Nov;30:1512-26). 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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848482.1

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

Description

The p.Arg249Cys (also known as p.Arg250Cys) variant in GCK has been reported in at least 6 individuals with maturity-onset diabetes of the young (MODY) and segregated with disease in at least 3 affected individuals from 1 family (Pruhova 2010 PMID: 20337973, Pinterova 2007 PMID: 17204055, Milenković 2008 PMID: 19069349, Osbak 2009 PMID: 19790256, Ma 2019 PMID: 30245511). This variant has also been reported in ClinVar (Variation ID 393451). It was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP3, PP1.

#	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: Oct 13, 2024

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