Variant: NM_000162.5(GCK):c.1175G>T (p.Arg392Leu)

CA213733

36185 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 073547fa-68db-4acb-940d-76d74c6084d7

Approved on: 2024-10-17

Published on: 2024-10-17

HGVS expressions

NM_000162.5:c.1175G>T
NM_000162.5(GCK):c.1175G>T (p.Arg392Leu)
NC_000007.14:g.44145575C>A
CM000669.2:g.44145575C>A
NC_000007.13:g.44185174C>A
CM000669.1:g.44185174C>A
NC_000007.12:g.44151699C>A
NG_008847.1:g.48849G>T
NG_008847.2:g.57596G>T
ENST00000395796.8:c.*1173G>T
ENST00000616242.5:c.*295G>T
ENST00000683378.1:n.401G>T
ENST00000336642.9:c.209G>T
ENST00000345378.7:c.1178G>T
ENST00000403799.8:c.1175G>T
ENST00000671824.1:c.1238G>T
ENST00000672743.1:n.187G>T
ENST00000673284.1:c.1175G>T
ENST00000336642.8:c.227G>T
ENST00000345378.6:c.1178G>T
ENST00000395796.7:c.1172G>T
ENST00000403799.7:c.1175G>T
ENST00000437084.1:c.1124G>T
ENST00000459642.1:n.555G>T
ENST00000616242.4:c.1172G>T
NM_000162.3:c.1175G>T
NM_033507.1:c.1178G>T
NM_033508.1:c.1172G>T
NM_000162.4:c.1175G>T
NM_001354800.1:c.1175G>T
NM_001354801.1:c.164G>T
NM_001354802.1:c.35G>T
NM_001354803.1:c.209G>T
NM_033507.2:c.1178G>T
NM_033508.2:c.1172G>T
NM_033507.3:c.1178G>T
NM_033508.3:c.1172G>T
NM_001354803.2:c.209G>T

Pathogenic

• Met criteria codes: PP1_Strong PS4_Moderate PP2 PM5_Supporting PP4_Moderate PM2_Supporting

• Not Met criteria codes: PP3

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.1175G>T variant in the glucokinase gene, GCK, causes an amino acid change of Arg to Leu at codon 392 (p.(Arg392Leu)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (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 has a REVEL score of 0.568, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function. Another missense variant, c.1174C>T p.Arg392Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg392Leu (PM5_Supporting). This variant was identified in 5 unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors). 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 a three generation family history) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 4 informative meioses in 2 families (PP1_Strong; internal lab contributors). In summary, c.1175G>T 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, PP2, PM5_Supporting, PS4_Moderate, PP4_Moderate, PP1_Strong.

Met criteria codes

• PP1_Strong: This variant segregated with diabetes/hyperglycemia, with 4 informative meioses in 2 families (PP1_Strong; internal lab contributors).
• PS4_Moderate: This variant was identified in 5 unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors).
• 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.1174C>T p.Arg392Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg392Leu (PM5_Supporting).
• 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 a three generation family history) (PP4_Moderate; internal lab contributors).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• PP3: This variant has a REVEL score of 0.568, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function.