NM_000162.5(GCK):c.787T>C (p.Ser263Pro) AND Maturity onset diabetes mellitus in young

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jan 18, 2019
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:: RCV000826166.9

Allele description [Variation Report for NM_000162.5(GCK):c.787T>C (p.Ser263Pro)]

NM_000162.5(GCK):c.787T>C (p.Ser263Pro)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.787T>C (p.Ser263Pro)

HGVS:

NC_000007.14:g.44147726A>G
NG_008847.2:g.55445T>C
NM_000162.5:c.787T>CMANE SELECT
NM_001354800.1:c.787T>C
NM_033507.3:c.790T>C
NM_033508.3:c.784T>C
NP_000153.1:p.Ser263Pro
NP_001341729.1:p.Ser263Pro
NP_277042.1:p.Ser264Pro
NP_277043.1:p.Ser262Pro
LRG_1074t1:c.787T>C
LRG_1074t2:c.790T>C
LRG_1074:g.55445T>C
LRG_1074p1:p.Ser263Pro
LRG_1074p2:p.Ser264Pro
NC_000007.13:g.44187325A>G
NM_000162.3:c.787T>C
NM_033508.1:c.784T>C
p.SER263PRO
p.Ser262Pro

Protein change:

S262P

Links:

dbSNP: rs193922331

NCBI 1000 Genomes Browser:

rs193922331

Molecular consequence:

NM_000162.5:c.787T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.787T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.790T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.784T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000967704	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Jan 18, 2019)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 16731834, 21831042, 21921030, 25555642, 12442280, 22820548, 24578721, 24033266
SCV002680996	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Dec 20, 2018)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 12442280, 14517946, 16731834, 19790256, 21831042, 22820548, 24568320, 29777474 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000967704

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Jan 18, 2019)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV002680996

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Dec 20, 2018)

germline

clinical testing

PubMed (8)
[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	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Generation of N-ethyl-N-nitrosourea (ENU) diabetes models in mice demonstrates genotype-specific action of glucokinase activators.

Fenner D, Odili S, Hong HK, Kobayashi Y, Kohsaka A, Siepka SM, Vitaterna MH, Chen P, Zelent B, Grimsby J, Takahashi JS, Matschinsky FM, Bass J.

J Biol Chem. 2011 Nov 11;286(45):39560-72. doi: 10.1074/jbc.M111.269100. Epub 2011 Sep 15.

PubMed [citation]

PMID:: 21921030
PMCID:: PMC3234779

Molecular genetic testing of patients with monogenic diabetes and hyperinsulinism.

Bennett JT, Vasta V, Zhang M, Narayanan J, Gerrits P, Hahn SH.

Mol Genet Metab. 2015 Mar;114(3):451-8. doi: 10.1016/j.ymgme.2014.12.304. Epub 2014 Dec 20.

PubMed [citation]

PMID:: 25555642
PMCID:: PMC7852340

See all PubMed Citations (12)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000967704.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (8)

Description

The p.Ser262Pro variant in GCK has been reported in at least 3 individuals with suspicion for MODY and segregated with disease in at least 3 affected members of two families (Cao 2002, Sagen 2006, GeneDx personal communication). It has also been identified in 1/128844 European chromosomes by gnomAD (http://gnomad.broad institute.org) and has been reported as likely pathogenic in ClinVar (Variation ID 36258). Computational prediction tools and conservation analysis do not provi de strong support for or against an impact to the protein. However, multiple in vitro functional studies suggest that this variant impacts protein function (Sag en 2006, Zelent 2011, Fenner 2011, Negahdar 2012, George 2014). In summary, alth ough additional studies are required to fully establish its clinical significanc e, the p.Ser262Pro variant meets criteria to be classified as likely pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PM2, PS3_Moderate, PP1, PS4_Supporting.

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

From Ambry Genetics, SCV002680996.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The p.S263P variant (also known as c.787T>C), located in coding exon 7 of the GCK gene, results from a T to C substitution at nucleotide position 787. The serine at codon 263 is replaced by proline, an amino acid with similar properties. This variant was identified in two maturity-onset diabetes of the young families (Cao H et al. Hum. Mutat., 2002 Dec;20:478-9; Sagen JV et al. Diabetes, 2006 Jun;55:1713-22). When stably over expressed in HEK293 cells and MIN6 cells, this variant generated a misfolded protein with an increased rate of degradation and a propensity to self-associate and form dimers and aggregates (Negahdar M et al. Biochim. Biophys. Acta, 2012 Nov;1822:1705-15). This amino acid position is poorly 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: Oct 13, 2024

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