Variant: NM_033508.3:c.627G>A

CA367401296

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 25ef58a4-42b3-4c2a-b7b3-309273022646

HGVS expressions

NM_033508.3:c.627G>A
NC_000007.14:g.44149809C>T
CM000669.2:g.44149809C>T
NC_000007.13:g.44189408C>T
CM000669.1:g.44189408C>T
NC_000007.12:g.44155933C>T
NG_008847.1:g.44615G>A
NG_008847.2:g.53362G>A
ENST00000395796.8:c.*628G>A
ENST00000616242.5:c.630G>A
ENST00000682635.1:n.1116G>A
ENST00000345378.7:c.633G>A
ENST00000403799.8:c.630G>A
ENST00000671824.1:c.630G>A
ENST00000673284.1:c.630G>A
ENST00000345378.6:c.633G>A
ENST00000395796.7:c.627G>A
ENST00000403799.7:c.630G>A
ENST00000437084.1:c.579G>A
ENST00000616242.4:c.627G>A
NM_000162.3:c.630G>A
NM_033507.1:c.633G>A
NM_033508.1:c.627G>A
NM_000162.4:c.630G>A
NM_001354800.1:c.630G>A
NM_033507.2:c.633G>A
NM_033508.2:c.627G>A
NM_000162.5:c.630G>A
NM_033507.3:c.633G>A

Pathogenic

• Met criteria codes: PS4_Moderate PM5_Strong PM2_Supporting PP3 PP2 PP1_Moderate 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 1.2.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.630G>A variant in the glucokinase gene, GCK, causes an amino acid change of methionine to isoleucine at codon 210 (p.(Met210Ile)) 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 0.9399, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate, internal lab contributors). Two of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies and/or persistent fasting hyperglycemia) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia, with 3 informative meioses in 2 families (PP1_Moderate; internal lab contributors). Two other missense variants, c.629T>A (p.Met210Lys) and c.629T>C (p.Met210Thr), have been classified as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.630G>A 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_Strong, PP1_Moderate, PP4_Moderate, PS4_Moderate, PP2, PP3, PM2_Supporting.

Met criteria codes

• PS4_Moderate: This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate, internal lab contributors).
• PM5_Strong: Two other missense variants, c.629T>A (p.Met210Lys) and c.629T>C (p.Met210Thr), have been classified as pathogenic by the ClinGen MDEP (PM5_Strong).
• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9399, which is greater than the MDEP 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).
• PP1_Moderate: This variant segregated with hyperglycemia, with 3 informative meioses in 2 families (PP1_Moderate; internal lab contributors).
• PP4_Moderate: This variant was identified in 2 unrelated individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies and/or persistent fasting hyperglycemia) (PP4_Moderate; internal lab contributors).

Approved on: 2024-01-22

Published on: 2024-01-22