NM_000162.5(GCK):c.787T>C (p.Ser263Pro) AND Maturity-onset diabetes of the young type 2

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jun 9, 2017
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:: RCV000029921.6

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 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000052576	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	likely pathogenic (Aug 18, 2011)	germline	curation, clinical testing	PubMed (5) [See all records that cite these PMIDs] 17186219, 14517946, 17389332, 12442280, 16731834 Citation Link,
SCV000882458	Translational Genomics Laboratory, University of Maryland School of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 9, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12442280, 22820548, 16731834, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000052576

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

likely pathogenic
(Aug 18, 2011)

germline

curation, clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV000882458

Translational Genomics Laboratory, University of Maryland School of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 9, 2017)

germline

clinical testing

PubMed (4)
[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	4	not provided	not provided	4	not provided	curation, clinical testing
not provided	germline	unknown	4	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity.

García-Herrero CM, Galán M, Vincent O, Flández B, Gargallo M, Delgado-Alvarez E, Blázquez E, Navas MA.

Diabetologia. 2007 Feb;50(2):325-33. Epub 2006 Dec 21.

PubMed [citation]

PMID:: 17186219

Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy.

Gloyn AL.

Hum Mutat. 2003 Nov;22(5):353-62. Review.

PubMed [citation]

PMID:: 14517946

See all PubMed Citations (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000052576.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	curation	PubMed (5)
2	not provided	1	not provided	not provided	curation	PubMed (5)
3	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)
4	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)
5	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)
6	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Converted during submission to Likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	3	not provided	not provided		3	not provided	not provided	not provided
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
3	germline	unknown	not provided	Blood	assert pathogenicity		not provided	not provided	not provided	See 3
4	germline	unknown	not provided	Blood	assert pathogenicity		not provided	not provided	not provided	See 4
5	germline	unknown	not provided	Blood	assert pathogenicity		not provided	not provided	not provided	See 5
6	germline	unknown	not provided	Blood	assert pathogenicity		not provided	not provided	not provided	See 6

Co-occurrences

#	Zygosity	Alleles	Number of Observations
3	SingleHeterozygote	TCF1:c.79A>C, TCF1:c.51C>G, TCF1:c.1545G>A, TCF1:c.1460G>A, TCF1:c.1375C>T, TCF1:c.864G>C, TCF1:c.1501+7G>A, TCF1:c.1720A>G, GCK:c.1253+8C>T	1
4	SingleHeterozygote	GCK:c.1253+8C>T, TCF1:c.79A>C, TCF1:c.1460G>A, TCF1:c.1375C>T, TCF1:c.51C>G, TCF1:c.1720A>G, TCF1:c.1501+7G>A, TCF1:c.293C>T	1
5	SingleHeterozygote	GCK:c.1253+8C>T	1
6	SingleHeterozygote	GCK:c.1253+8C>T	1

From Translational Genomics Laboratory, University of Maryland School of Medicine, SCV000882458.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The c.787T>C variant in codon 263 (exon 7) of the glucokinase gene, GCK, results in the substitution of Serine to a Proline. The c.787T>C 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 whose clinical picture is consistent with Maturity-Onset Diabetes of the Young (MODY) (12442280). Functional analyses of this variant have demonstrated thermal instability, protein misfolding and aberrant dimerization (22820548;16731834). Additionally, multiple lines of computational evidence (SIFT, MutationTaster, FATHMM, MetaSVM, MetaLR, CADD) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG criteria = PS3, 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: Oct 13, 2024

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