Variant: NM_000162.5(GCK):c.1130G>T (p.Arg377Leu)

CA367398811

872751 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 4e31cb0e-179d-4e9f-b019-06da4e8bc75c

Approved on: 2023-11-24

Published on: 2023-11-24

HGVS expressions

NM_000162.5:c.1130G>T
NM_000162.5(GCK):c.1130G>T (p.Arg377Leu)
NC_000007.14:g.44145620C>A
CM000669.2:g.44145620C>A
NC_000007.13:g.44185219C>A
CM000669.1:g.44185219C>A
NC_000007.12:g.44151744C>A
NG_008847.1:g.48804G>T
NG_008847.2:g.57551G>T
ENST00000395796.8:c.*1128G>T
ENST00000616242.5:c.*250G>T
ENST00000683378.1:n.356G>T
ENST00000336642.9:c.164G>T
ENST00000345378.7:c.1133G>T
ENST00000403799.8:c.1130G>T
ENST00000671824.1:c.1193G>T
ENST00000672743.1:n.142G>T
ENST00000673284.1:c.1130G>T
ENST00000336642.8:c.182G>T
ENST00000345378.6:c.1133G>T
ENST00000395796.7:c.1127G>T
ENST00000403799.7:c.1130G>T
ENST00000437084.1:c.1079G>T
ENST00000459642.1:n.510G>T
ENST00000616242.4:c.1127G>T
NM_000162.3:c.1130G>T
NM_033507.1:c.1133G>T
NM_033508.1:c.1127G>T
NM_000162.4:c.1130G>T
NM_001354800.1:c.1130G>T
NM_001354801.1:c.119G>T
NM_001354802.1:c.-11G>T
NM_001354803.1:c.164G>T
NM_033507.2:c.1133G>T
NM_033508.2:c.1127G>T
NM_033507.3:c.1133G>T
NM_033508.3:c.1127G>T
NM_001354803.2:c.164G>T

Likely Pathogenic

• Met criteria codes: PP4_Moderate PS4_Moderate PP3 PP2 PM5_Supporting 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 1.0.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1130G>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to leucine at codon 377 (p.(Arg377Leu)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are 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 is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in five unrelated individuals with hyperglycemia (PS4_Moderate: PMIDs: 21348868, 30245511, internal lab contributors). At least 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 OGTT increment < 3.0 mmol/L or negative antibodies) (PP4_Moderate; internal lab contributors). Another missense variant, c.1129C>T p.(Arg377Cys), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.(Arg377Leu). Another missense variant, c.1129C>A p.Arg377Ser, has been classified as likely pathogenic by the ClinGen MDEP VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023) : PS4_Moderate, PP2, PP3, PM2_Supporting, PP4_Moderate, PM5_Supporting.

Met criteria codes

• PP4_Moderate: This variant was identified in two individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3.0 mmol/L or negative antibodies) (PP4_Moderate; internal lab contributors).
• PS4_Moderate: This variant was identified in five unrelated individuals with hyperglycemia (PMIDs: 21348868, 30245511, 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).
• PM5_Supporting: Another missense variant, c.1129C>T p.Arg377Cys), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.Arg377His). Another missense variant, c.1129C>A p.Arg377Ser, has been classified as likely pathogenic by the ClinGen MDEP VCEP (PM5_Supporting).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).