Variant: NM_000162.5(GCK):c.523G>A (p.Gly175Arg)

CA231137

129143 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 4b2ceaad-8826-45d2-bf5d-9ff4c035568d

Approved on: 2023-07-30

Published on: 2023-07-30

HGVS expressions

NM_000162.5:c.523G>A
NM_000162.5(GCK):c.523G>A (p.Gly175Arg)
NC_000007.14:g.44150025C>T
CM000669.2:g.44150025C>T
NC_000007.13:g.44189624C>T
CM000669.1:g.44189624C>T
NC_000007.12:g.44156149C>T
NG_008847.1:g.44399G>A
NG_008847.2:g.53146G>A
ENST00000395796.8:c.*521G>A
ENST00000616242.5:c.523G>A
ENST00000682635.1:n.1009G>A
ENST00000345378.7:c.526G>A
ENST00000403799.8:c.523G>A
ENST00000671824.1:c.523G>A
ENST00000673284.1:c.523G>A
ENST00000345378.6:c.526G>A
ENST00000395796.7:c.520G>A
ENST00000403799.7:c.523G>A
ENST00000437084.1:c.472G>A
ENST00000616242.4:n.520G>A
NM_000162.3:c.523G>A
NM_033507.1:c.526G>A
NM_033508.1:c.520G>A
NM_000162.4:c.523G>A
NM_001354800.1:c.523G>A
NM_033507.2:c.526G>A
NM_033508.2:c.520G>A
NM_033507.3:c.526G>A
NM_033508.3:c.520G>A

Pathogenic

• Met criteria codes: PS3_Supporting PP1_Strong PM2_Supporting PP3 PP2 PP4_Moderate PS1 PS4

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 1.1.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.523G>A variant in the glucokinase gene, GCK causes an amino acid change of Gly to Arg at codon 210 (p.(Gly175Arg)) 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 also predicted to be deleterious by computational evidence, with a REVEL score of 0.965, 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 8 unrelated individuals with diabetes (PS4; PMID: 29944009, 20337973, 26552609, 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/hyperglycemia) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with 5 informative meioses in 4 families with diabetes (PP1_Strong; internal lab contributors). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, but the wild-type ATP Km is not between 0.4-0.65, and the p.Gly175Arg variant has Kcat/S0.5<0.5 (PS3_Supporting; PMID 10525657). The nucleotide change c.523G>C, which causes the same amino acid change, has been classified as pathogenic for MODY by the ClinGen MDEP (PS1). In summary, this variant meets the criteria to be classified as Pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023) : PS4, PP1_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, PP2, PP3, PS1.

Met criteria codes

• PS3_Supporting: A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, but the wild-type ATP Km is not between 0.4-0.65, and the p.Gly175Arg variant has Kcat/S0.5<0.5 (PS3_Supporting; PMID 10525657).
• PP1_Strong: This variant segregated with diabetes with 5 informative meioses in 4 families with diabetes (PP1_Strong; internal lab contributors).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.965, 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).
• 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/hyperglycemia) (PP4_Moderate; internal lab contributors).
• PS1: The nucleotide change c.523G>C, which causes the same amino acid change, has been classified as pathogenic for MODY by the ClinGen MDEP (PS1).
• PS4: This variant was identified in 8 unrelated individuals with diabetes (PS4; PMID: 29944009, 20337973, 26552609, internal lab contributors).