Variant: NM_033508.3:c.458T>G

CA367401907

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 68140ef7-889c-4017-aacc-dd8c9fb840ca

Approved on: 2023-12-08

Published on: 2023-12-08

HGVS expressions

NM_033508.3:c.458T>G
NC_000007.14:g.44150978A>C
CM000669.2:g.44150978A>C
NC_000007.13:g.44190577A>C
CM000669.1:g.44190577A>C
NC_000007.12:g.44157102A>C
NG_008847.1:g.43446T>G
NG_008847.2:g.52193T>G
ENST00000395796.8:c.*459T>G
ENST00000616242.5:c.461T>G
ENST00000682635.1:n.947T>G
ENST00000345378.7:c.464T>G
ENST00000403799.8:c.461T>G
ENST00000671824.1:c.461T>G
ENST00000673284.1:c.461T>G
ENST00000345378.6:c.464T>G
ENST00000395796.7:c.458T>G
ENST00000403799.7:c.461T>G
ENST00000437084.1:c.410T>G
ENST00000616242.4:c.458T>G
NM_000162.3:c.461T>G
NM_033507.1:c.464T>G
NM_033508.1:c.458T>G
NM_000162.4:c.461T>G
NM_001354800.1:c.461T>G
NM_033507.2:c.464T>G
NM_033508.2:c.458T>G
NM_000162.5:c.461T>G
NM_033507.3:c.464T>G

Likely Pathogenic

• Met criteria codes: PP3 PP2 PP4_Moderate PS2_Moderate 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.461T>G variant in the glucokinase gene, GCK, causes an amino acid change of valine to glycine at codon 154 (p.(Val154Gly)) of NM_000162.5. 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 negative antibodies) (PP4_Moderate; internal lab contributors). This variant was identified as a de novo occurrence with unconfirmed parental relationships in an individual with diabetes, whose clinical picture is highly specific for GCK-hyperglycemia (PS2_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 0.953, 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.461T>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, PS2_Moderate, PP2, PP3, PM2_Supporting.

Met criteria codes

• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.953, 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 negative antibodies) (PP4_Moderate; internal lab contributors).
• PS2_Moderate: This variant was identified as a de novo occurrence with unconfirmed parental relationships in an individual with diabetes, whose clinical picture is highly specific for GCK-MODY (PS2_Moderate) internal lab contributor).
• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).