Variant: NM_000162.5(GCK):c.171G>A (p.Met57Ile)

CA16618473

418225 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 4a8438c3-ee89-4425-8ff0-db3060cc9b0a

Approved on: 2025-02-28

Published on: 2025-02-28

HGVS expressions

NM_000162.5:c.171G>A
NM_000162.5(GCK):c.171G>A (p.Met57Ile)
NC_000007.14:g.44153338C>T
CM000669.2:g.44153338C>T
NC_000007.13:g.44192937C>T
CM000669.1:g.44192937C>T
NC_000007.12:g.44159462C>T
NG_008847.1:g.41086G>A
NG_008847.2:g.49833G>A
ENST00000395796.8:c.*169G>A
ENST00000616242.5:c.171G>A
ENST00000682635.1:n.657G>A
ENST00000345378.7:c.174G>A
ENST00000403799.8:c.171G>A
ENST00000671824.1:c.171G>A
ENST00000673284.1:c.171G>A
ENST00000345378.6:c.174G>A
ENST00000395796.7:c.168G>A
ENST00000403799.7:c.171G>A
ENST00000437084.1:c.171G>A
ENST00000616242.4:c.168G>A
NM_000162.3:c.171G>A
NM_033507.1:c.174G>A
NM_033508.1:c.168G>A
NM_000162.4:c.171G>A
NM_001354800.1:c.171G>A
NM_033507.2:c.174G>A
NM_033508.2:c.168G>A
NM_033507.3:c.174G>A
NM_033508.3:c.168G>A

Pathogenic

• Met criteria codes: PS4_Moderate PM2_Supporting PS2 PP1 PP3 PP2 PP4_Moderate

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.171G>A variant in the glucokinase gene, GCK, causes an amino acid change of methionine to isoleucine at codon 57 (p.(Met57Ile)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). 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 0.988, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 5 unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 24323243, internal lab contributors). In one of these individuals this variant was identified as a de novo occurrence with confirmed parental relationships and a clinical picture higly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L, HbA1c 5.6-7.6 and negative autoantibodies) (PS2, PP4_Moderate; PMID: 24323243). This variant segregated with hyperglycemia, with 2 informative meioses in two families (PP1; internal lab contributors). In summary, c.170T>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): PM2_Supporting, PP1, PP2, PP3, PP4_Moderate, PS2).

Met criteria codes

• PS4_Moderate: This variant was identified in 5 unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 24323243, internal lab contributors).
• PM2_Supporting: This variant is absent from gnomAD v2.1 and v4.1 (PM2_Supporting).
• PS2: This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with a clinical picture consistent with GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6-7.6) (PS2; PMID: 24323243)
• PP1: This variant segregated with hyperglycemia, with 2 informative meioses in two families (PP1; internal lab contributors).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.988, 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; PMID: 24323243).