NM_000162.5(GCK):c.1240A>G (p.Lys414Glu) AND Monogenic diabetes

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 26, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV001248969.5

Allele description [Variation Report for NM_000162.5(GCK):c.1240A>G (p.Lys414Glu)]

NM_000162.5(GCK):c.1240A>G (p.Lys414Glu)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.1240A>G (p.Lys414Glu)

Other names:

NM_000162.5(GCK):c.1240A>G

HGVS:

NC_000007.14:g.44145510T>C
NG_008847.2:g.57661A>G
NM_000162.5:c.1240A>GMANE SELECT
NM_001354800.1:c.1240A>G
NM_001354801.1:c.229A>G
NM_001354802.1:c.100A>G
NM_001354803.2:c.274A>G
NM_033507.3:c.1243A>G
NM_033508.3:c.1237A>G
NP_000153.1:p.Lys414Glu
NP_001341729.1:p.Lys414Glu
NP_001341730.1:p.Lys77Glu
NP_001341731.1:p.Lys34Glu
NP_001341732.1:p.Lys92Glu
NP_277042.1:p.Lys415Glu
NP_277043.1:p.Lys413Glu
LRG_1074t1:c.1240A>G
LRG_1074t2:c.1243A>G
LRG_1074:g.57661A>G
LRG_1074p1:p.Lys414Glu
LRG_1074p2:p.Lys415Glu
NC_000007.13:g.44185109T>C
NM_000162.3(GCK):c.1240A>G
NM_000162.3:c.1240A>G
P35557:p.Lys414Glu

Protein change:

K34E

Links:

UniProtKB: P35557#VAR_003714; dbSNP: rs193922272

NCBI 1000 Genomes Browser:

rs193922272

Molecular consequence:

NM_000162.5:c.1240A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.1240A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354801.1:c.229A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354802.1:c.100A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354803.2:c.274A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.1243A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.1237A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001422801	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 22, 2020)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 8325892, 10525657, 25741868 Citation Link,
SCV004012147	ClinGen Monogenic Diabetes Variant Curation Expert Panel	reviewed by expert panel (ClinGen Diabetes ACMG Specifications GCK V1.2.0)	Pathogenic (Jun 26, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001422801

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 22, 2020)

germline

curation

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV004012147

ClinGen Monogenic Diabetes Variant Curation Expert Panel

reviewed by expert panel

(ClinGen Diabetes ACMG Specifications GCK V1.2.0)

Pathogenic
(Jun 26, 2023)

germline

curation

Citation Link

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	curation

Citations

PubMed

Structure/function studies of human beta-cell glucokinase. Enzymatic properties of a sequence polymorphism, mutations associated with diabetes, and other site-directed mutants.

Takeda J, Gidh-Jain M, Xu LZ, Froguel P, Velho G, Vaxillaire M, Cohen D, Shimada F, Makino H, Nishi S, et al.

J Biol Chem. 1993 Jul 15;268(20):15200-4.

PubMed [citation]

PMID:: 8325892

Mutants of glucokinase cause hypoglycaemia- and hyperglycaemia syndromes and their analysis illuminates fundamental quantitative concepts of glucose homeostasis.

Davis EA, Cuesta-Muñoz A, Raoul M, Buettger C, Sweet I, Moates M, Magnuson MA, Matschinsky FM.

Diabetologia. 1999 Oct;42(10):1175-86.

PubMed [citation]

PMID:: 10525657

See all PubMed Citations (3)

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422801.2

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

Description

The p.Lys414Glu variant in GCK has been reported in at least one individual with Monogenic Diabetes (PMID: 8433729), and was absent from large population studies. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 36188). In vitro functional studies provide some evidence that the p.Lys414Glu variant may impact protein binding and activity (PMID: 21831042, 8325892, 10525657). However, these types of assays may not accurately represent biological function. Animal models in mice have shown that this variant causes Monogenic Diabetes (PMID: 17353190). 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 is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PP3 (Richards 2015).

#	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 ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV004012147.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The c.1240A>G variant in the glucokinase gene, GCK, causes an amino acid change of lysine to glutamic acid at codon 414 (p.(Lys414Glu)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.9279, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in seven unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; ClinVar ID 36188, PMID 18411240, internal lab contributors). The variant segregated with diabetes, with 5 informative meioses in three families with MODY (PP1_Strong; internal lab contributors). Additionally, one of these individuals has a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributor). In summary, c.1240A>G meets the criteria to be classified as pathogenic by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP1_Strong, PS4, PP4, PM1, PP2, PP3, PM2_Supporting.

#	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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