Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

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

CA16605802

381598 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

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

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

PM2_Supporting PS4 PP3 PP2 PP4 PP1_Strong

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

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.

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 ).

PP1_Strong

This variant segregated with diabetes with 4 informative meioses in 3 families with diabetes (PP1_Strong; PMID 27256595, 9049484, internal lab contributors).

Approved on: 2023-08-09

Published on: 2023-08-10

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.