NM_000162.5(GCK):c.109A>G (p.Met37Val) AND Monogenic diabetes

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Nov 22, 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:: RCV003445456.2

Allele description [Variation Report for NM_000162.5(GCK):c.109A>G (p.Met37Val)]

NM_000162.5(GCK):c.109A>G (p.Met37Val)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.109A>G (p.Met37Val)

Other names:

NM_033508.3:c.106A>G

HGVS:

NC_000007.14:g.44153400T>C
NG_008847.2:g.49771A>G
NM_000162.5:c.109A>GMANE SELECT
NM_001354800.1:c.109A>G
NM_033507.3:c.112A>G
NM_033508.3:c.106A>G
NP_000153.1:p.Met37Val
NP_001341729.1:p.Met37Val
NP_277042.1:p.Met38Val
NP_277043.1:p.Met36Val
LRG_1074t1:c.109A>G
LRG_1074t2:c.112A>G
LRG_1074:g.49771A>G
LRG_1074p1:p.Met37Val
LRG_1074p2:p.Met38Val
NC_000007.13:g.44192999T>C

Protein change:

M36V

Molecular consequence:

NM_000162.5:c.109A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.109A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.112A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.106A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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PEBP (phosphatidylethanolamine-binding protein) family protein [Arabidopsis thal...
PEBP (phosphatidylethanolamine-binding protein) family protein [Arabidopsis thaliana]
gi|15237061|ref|NP_193770.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004174225	ClinGen Monogenic Diabetes Variant Curation Expert Panel	reviewed by expert panel (ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)	Likely pathogenic (Nov 22, 2023)	germline	curation	Citation Link,
SCV004223350	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Nov 6, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004174225

ClinGen Monogenic Diabetes Variant Curation Expert Panel

reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)

Likely pathogenic
(Nov 22, 2023)

germline

curation

Citation Link,

SCV004223350

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Nov 6, 2023)

germline

clinical testing

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	clinical testing, curation

Details of each submission

From ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV004174225.1

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

Description

The c.109A>G variant in the glucokinase gene, GCK, causes an amino acid change of methionine to valine at codon 37 (p.(Met37Val)) of NM_000162.5.This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributor). 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 is predicted to be deleterious by computational evidence, with a REVEL score of 0.8759, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.110T>G (p.Met37Arg) has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Met37Val (PM5_Supporting). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918; internal lab contributor). In summary, c.109A>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PP2, PP3, PM2_Supporting, PM5_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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004223350.1

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

Description

Variant summary: GCK c.109A>G (p.Met37Val) results in a conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251464 control chromosomes. c.109A>G has been observed in at-least one family with three affected individuals that reportedly fulfill the criteria for GCK associated Monogenic Diabetes (antibody negative, personel correspondence with MODY Expert Panel). However, to our knowledge, it has not been reported in the literature in individuals affected with Monogenic Diabetes. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant located at the same codon, namely c.109A>G (p.Met37Val) has been classified as pathogenic by the Clingen MODY expert panel (ClinVar ID 2578357) supporting a critical relevance of this Methionine reside to GCK protein function. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above and in accordance with the Clingen MODY specifications, the variant was classified as likely 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: Jan 6, 2024

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