Variant: NM_001354803.2:c.176T>C

CA367398764

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 14308ead-6fe4-4f40-9c9b-97a88a082693

Approved on: 2023-07-17

Published on: 2023-07-17

HGVS expressions

NM_001354803.2:c.176T>C
NC_000007.14:g.44145608A>G
CM000669.2:g.44145608A>G
NC_000007.13:g.44185207A>G
CM000669.1:g.44185207A>G
NC_000007.12:g.44151732A>G
NG_008847.1:g.48816T>C
NG_008847.2:g.57563T>C
ENST00000395796.8:c.*1140T>C
ENST00000616242.5:c.*262T>C
ENST00000683378.1:n.368T>C
ENST00000336642.9:c.176T>C
ENST00000345378.7:c.1145T>C
ENST00000403799.8:c.1142T>C
ENST00000671824.1:c.1205T>C
ENST00000672743.1:n.154T>C
ENST00000673284.1:c.1142T>C
ENST00000336642.8:n.194T>C
ENST00000345378.6:c.1145T>C
ENST00000395796.7:c.1139T>C
ENST00000403799.7:c.1142T>C
ENST00000437084.1:c.1091T>C
ENST00000459642.1:n.522T>C
ENST00000616242.4:n.1139T>C
NM_000162.3:c.1142T>C
NM_033507.1:c.1145T>C
NM_033508.1:c.1139T>C
NM_000162.4:c.1142T>C
NM_001354800.1:c.1142T>C
NM_001354801.1:c.131T>C
NM_001354802.1:c.2T>C
NM_001354803.1:c.176T>C
NM_033507.2:c.1145T>C
NM_033508.2:c.1139T>C
NM_000162.5:c.1142T>C
NM_033507.3:c.1145T>C
NM_033508.3:c.1139T>C

Pathogenic

• Met criteria codes: PP1_Strong PP4_Moderate PM2_Supporting PS4 PP3 PP2

• Not Met criteria codes: PS3

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.1142T>C variant in the glucokinase gene, GCK, causes an amino acid change of methionine to threonine at codon 381 (p.(Met381Thr)) 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 0.93, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 30257192). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in at least 18 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID 30257192, internal lab contributors). At least 5 of these individuals have 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 contributors). Additionally, this variant segregated with diabetes, with at least 16 informative meioses in 6 families with MODY (PP1_Strong; PMID 30257192, internal lab contributors). In summary, the c.1142T>C variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP1_Strong, PP4_Moderate, PS4, PP2, PP3, PM2_Supporting.

Met criteria codes

• PP1_Strong: This variant segregated with diabetes, with at least 16 informative meioses in 6 families with MODY (PP1_Strong; PMID 30257192, internal lab contributors).
• PP4_Moderate: This variant was identified in at least 5 individuals 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 contributors).
• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
• PS4: This variant was identified in at least 18 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID 30257192, internal contributors).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.93, 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).

Not Met criteria codes

• PS3: While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 30257192).