Variant: NM_033508.3:c.602T>G

CA367401376

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 72d1c915-4d9b-498b-8b28-b716ca0bb3ed

Approved on: 2024-04-19

Published on: 2024-04-19

HGVS expressions

NM_033508.3:c.602T>G
NC_000007.14:g.44149834A>C
CM000669.2:g.44149834A>C
NC_000007.13:g.44189433A>C
CM000669.1:g.44189433A>C
NC_000007.12:g.44155958A>C
NG_008847.1:g.44590T>G
NG_008847.2:g.53337T>G
ENST00000395796.8:c.*603T>G
ENST00000616242.5:c.605T>G
ENST00000682635.1:n.1091T>G
ENST00000345378.7:c.608T>G
ENST00000403799.8:c.605T>G
ENST00000671824.1:c.605T>G
ENST00000673284.1:c.605T>G
ENST00000345378.6:c.608T>G
ENST00000395796.7:c.602T>G
ENST00000403799.7:c.605T>G
ENST00000437084.1:c.554T>G
ENST00000616242.4:c.602T>G
NM_000162.3:c.605T>G
NM_033507.1:c.608T>G
NM_033508.1:c.602T>G
NM_000162.4:c.605T>G
NM_001354800.1:c.605T>G
NM_033507.2:c.608T>G
NM_033508.2:c.602T>G
NM_000162.5:c.605T>G
NM_033507.3:c.608T>G

Pathogenic

• Met criteria codes: PM5 PP4_Moderate PM2_Supporting PP1_Moderate PS4 PP3 PP2

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 1.3.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.605T>G variant in the glucokinase gene, GCK, causes an amino acid change of methionine to arginine at codon 202 (p.(Met202Arg)) 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 is predicted to be deleterious by computational evidence, with a REVEL score of 0.969, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; internal lab contributors). This variant segregated with diabetes, with 3 informative meioses in 2 families with MODY (PP1_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and three-generation, dominant family history of diabetes or hyperglycemia in a family not used for PP1) (PP4_Moderate; internal lab contributors). Another missense variant, c.605T>C p.Met202Thr has been interpreted as pathogenic by the ClinGen MDEP, and p.Met202Arg has an equal or greater Grantham distance (PM5). In summary, c.605T>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): PM5, PS4, PP4_Moderate, PP1_Moderate, PM2_Supporting, PP2, PP3.

Met criteria codes

• PM5: Another missense variant, c.605T>C p.Met202Thr has been interpreted as pathogenic by the ClinGen MDEP, and p.Met202Arg has an equal or greater Grantham distance (PM5).
• PP4_Moderate: This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and three-generation, dominant family history of diabetes or hyperglycemia in a family not used for PP1) (PP4_Moderate; internal lab contributors).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PP1_Moderate: This variant segregated with diabetes, with 3 informative meioses in 2 families with MODY (PP1_Moderate; internal lab contributors).
• PS4: GCK: This variant was identified in 7 unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.969, 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).