Variant: NM_000162.5(GCK):c.1099G>A (p.Val367Met)

CA16605802

381598 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: e7250528-78fc-4419-81da-e7b6d944fc80

Approved on: 2023-08-09

Published on: 2023-08-10

HGVS expressions

NM_000162.5:c.1099G>A
NM_000162.5(GCK):c.1099G>A (p.Val367Met)
NC_000007.14:g.44145651C>T
CM000669.2:g.44145651C>T
NC_000007.13:g.44185250C>T
CM000669.1:g.44185250C>T
NC_000007.12:g.44151775C>T
NG_008847.1:g.48773G>A
NG_008847.2:g.57520G>A
ENST00000395796.8:c.*1097G>A
ENST00000616242.5:c.*219G>A
ENST00000683378.1:n.325G>A
ENST00000336642.9:c.133G>A
ENST00000345378.7:c.1102G>A
ENST00000403799.8:c.1099G>A
ENST00000671824.1:c.1162G>A
ENST00000672743.1:n.111G>A
ENST00000673284.1:c.1099G>A
ENST00000336642.8:n.151G>A
ENST00000345378.6:c.1102G>A
ENST00000395796.7:c.1096G>A
ENST00000403799.7:c.1099G>A
ENST00000437084.1:c.1048G>A
ENST00000459642.1:n.479G>A
ENST00000473353.1:n.397G>A
ENST00000616242.4:n.1096G>A
NM_000162.3:c.1099G>A
NM_033507.1:c.1102G>A
NM_033508.1:c.1096G>A
NM_000162.4:c.1099G>A
NM_001354800.1:c.1099G>A
NM_001354801.1:c.88G>A
NM_001354802.1:c.-42G>A
NM_001354803.1:c.133G>A
NM_033507.2:c.1102G>A
NM_033508.2:c.1096G>A
NM_033507.3:c.1102G>A
NM_033508.3:c.1096G>A
NM_001354803.2:c.133G>A

Pathogenic

• Met criteria codes: PP1_Strong PM2_Supporting PS4 PP3 PP2 PP4

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.1099G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 367 (p.(Val367Met)) 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 0.929, 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 7 unrelated individuals with diabetes/hyperglycemia (PS4; PMID 27256595, 31968686, 9049484, internal lab contributors). This variant segregated with diabetes with 4 informative meioses in 3 families with diabetes/hyperglycemia (PP1_Strong; PMID 27256595, 9049484, 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%) (PP4; PMID 27256595 ). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PS4, PP4, PP1_Strong.

Met criteria codes

• PP1_Strong: This variant segregated with diabetes with 4 informative meioses in 3 families with diabetes (PP1_Strong; PMID 27256595, 9049484, internal lab contributors).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PS4: This variant was identified in 7 unrelated individuals with diabetes/hyperglycemia (PS4; PMID 27256595, 31968686, 9049484, internal lab contributors)
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.929, 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: 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%) (PP4; PMID 27256595 ).