Variant: NM_033508.3:c.107T>G

CA367403541

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: cc7cd78c-8711-4e90-9c33-9b965a05da5d

Approved on: 2023-08-25

Published on: 2023-08-25

HGVS expressions

NM_033508.3:c.107T>G
NC_000007.14:g.44153399A>C
CM000669.2:g.44153399A>C
NC_000007.13:g.44192998A>C
CM000669.1:g.44192998A>C
NC_000007.12:g.44159523A>C
NG_008847.1:g.41025T>G
NG_008847.2:g.49772T>G
ENST00000395796.8:c.*108T>G
ENST00000616242.5:c.110T>G
ENST00000682635.1:n.596T>G
ENST00000345378.7:c.113T>G
ENST00000403799.8:c.110T>G
ENST00000671824.1:c.110T>G
ENST00000673284.1:c.110T>G
ENST00000345378.6:c.113T>G
ENST00000395796.7:c.107T>G
ENST00000403799.7:c.110T>G
ENST00000437084.1:c.110T>G
ENST00000476008.1:n.545T>G
ENST00000616242.4:n.107T>G
NM_000162.3:c.110T>G
NM_033507.1:c.113T>G
NM_033508.1:c.107T>G
NM_000162.4:c.110T>G
NM_001354800.1:c.110T>G
NM_033507.2:c.113T>G
NM_033508.2:c.107T>G
NM_000162.5:c.110T>G
NM_033507.3:c.113T>G

Pathogenic

• Met criteria codes: PP4_Moderate PS4_Moderate PP3 PP2 PP1_Strong PM2_Supporting

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 1.2.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.110T>G variant in the glucokinase gene,GCK, causes an amino acid change of methionine to arginine at codon 37 (p.(Met37Arg)) of NM_000162.5. This variant segregated with diabetes, with at least four informative meioses in two families with MODY (PP1_Strong; internal lab contributors). 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 an OGTT with minimal increment) (PP4_Moderate; internal lab contributor). This variant was identified in four unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributor, DOI: 10.1055/s-2008-1004713). 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 0.9739, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). In summary, c.110T>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PP4_Moderate, PS4_Moderate, PP2, PP3, PM2_Supporting.

Met criteria codes

• PP4_Moderate: 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 an OGTT with minimal increment) (PP4_Moderate; internal lab contributor).
• PS4_Moderate: This variant was identified in four unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributor, DOI: 10.1055/s-2008-1004713).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9739, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
• PP2: 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).
• PP1_Strong: This variant segregated with diabetes, with at least four informative meioses in two families with MODY (PP1_Strong; internal lab contributors).
• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).