NM_000162.5(GCK):c.952G>A (p.Gly318Arg) AND Monogenic diabetes

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Dec 23, 2021
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:: RCV001805831.2

Allele description [Variation Report for NM_000162.5(GCK):c.952G>A (p.Gly318Arg)]

NM_000162.5(GCK):c.952G>A (p.Gly318Arg)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.952G>A (p.Gly318Arg)

HGVS:

NC_000007.14:g.44146530C>T
NG_008847.2:g.56641G>A
NM_000162.5:c.952G>AMANE SELECT
NM_001354800.1:c.952G>A
NM_001354801.1:c.8+89G>A
NM_033507.3:c.955G>A
NM_033508.3:c.949G>A
NP_000153.1:p.Gly318Arg
NP_001341729.1:p.Gly318Arg
NP_277042.1:p.Gly319Arg
NP_277043.1:p.Gly317Arg
LRG_1074t1:c.952G>A
LRG_1074t2:c.955G>A
LRG_1074:g.56641G>A
LRG_1074p1:p.Gly318Arg
LRG_1074p2:p.Gly319Arg
NC_000007.13:g.44186129C>T
NM_000162.3:c.952G>A

Protein change:

G317R

Links:

dbSNP: rs193922340

NCBI 1000 Genomes Browser:

rs193922340

Molecular consequence:

NM_001354801.1:c.8+89G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000162.5:c.952G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.952G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.955G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.949G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Monogenic diabetes
Identifiers:: MONDO: MONDO:0015967; MedGen: C3888631

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002051328	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 23, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12627330, 14517956, 16602010, 22332836, 34440516, 22493702 Citation Link,
SCV002761528	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 18, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002051328

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Dec 23, 2021)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV002761528

Genetics and Molecular Pathology, SA Pathology

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 18, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Citations

PubMed

Genetic epidemiology of MODY in the Czech republic: new mutations in the MODY genes HNF-4alpha, GCK and HNF-1alpha.

Pruhova S, Ek J, Lebl J, Sumnik Z, Saudek F, Andel M, Pedersen O, Hansen T.

Diabetologia. 2003 Feb;46(2):291-5. Epub 2003 Jan 8.

PubMed [citation]

PMID:: 12627330

Identification of 21 novel glucokinase (GCK) mutations in UK and European Caucasians with maturity-onset diabetes of the young (MODY).

Thomson KL, Gloyn AL, Colclough K, Batten M, Allen LI, Beards F, Hattersley AT, Ellard S.

Hum Mutat. 2003 Nov;22(5):417.

PubMed [citation]

PMID:: 14517956

See all PubMed Citations (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002051328.1

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

Description

Variant summary: GCK c.952G>A (p.Gly318Arg) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 247788 control chromosomes. c.952G>A has been reported in the literature in multiple individuals affected with Monogenic Diabetes presenting as MODY2 (Maturity Onset Diabetes of the Young) (example, Thomson_2003, Pruhova_2003, Feigeriova_2006, Dustakova_2012, Valentinova_2012, Gal_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as 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 Genetics and Molecular Pathology, SA Pathology, SCV002761528.1

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

#	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: May 7, 2024

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