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_001354803.2:c.146G>A

CA367398935

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: b1d7557e-5fd6-45dd-86a1-c5c03cf413b9

HGVS expressions

NM_001354803.2:c.146G>A

NC_000007.14:g.44145638C>T

CM000669.2:g.44145638C>T

NC_000007.13:g.44185237C>T

CM000669.1:g.44185237C>T

NC_000007.12:g.44151762C>T

NG_008847.1:g.48786G>A

NG_008847.2:g.57533G>A

ENST00000395796.8:c.*1110G>A

ENST00000616242.5:c.*232G>A

ENST00000683378.1:n.338G>A

ENST00000336642.9:c.146G>A

ENST00000345378.7:c.1115G>A

ENST00000403799.8:c.1112G>A

ENST00000671824.1:c.1175G>A

ENST00000672743.1:n.124G>A

ENST00000673284.1:c.1112G>A

ENST00000336642.8:n.164G>A

ENST00000345378.6:c.1115G>A

ENST00000395796.7:c.1109G>A

ENST00000403799.7:c.1112G>A

ENST00000437084.1:c.1061G>A

ENST00000459642.1:n.492G>A

ENST00000616242.4:n.1109G>A

NM_000162.3:c.1112G>A

NM_033507.1:c.1115G>A

NM_033508.1:c.1109G>A

NM_000162.4:c.1112G>A

NM_001354800.1:c.1112G>A

NM_001354801.1:c.101G>A

NM_001354802.1:c.-29G>A

NM_001354803.1:c.146G>A

NM_033507.2:c.1115G>A

NM_033508.2:c.1109G>A

NM_000162.5:c.1112G>A

NM_033507.3:c.1115G>A

NM_033508.3:c.1109G>A

Likely Pathogenic

PM2 PM5_Supporting PP1_Strong PP3 PP2

PP4

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.1112G>A variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to tyrosine at codon 371 (p.(Cys371Tyr)) 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 0.956, 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 segregated with diabetes with 5 informative meioses in a family with diabetes/hyperglycemia (PP1_Strong; internal lab contributors). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). Another missense variant, c.1112G>T p.(Cys371Phe), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.(Cys371Tyr)(PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for GENE-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PP1_Strong, PM5_Supporting.

PM2

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

PM5_Supporting

Another missense variant, c.1112G>T p.(Cys371Phe) , has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.(Cys371Tyr)(PM5_Supporting).

PP1_Strong

This variant segregated with diabetes with 5 informative meioses in a family with diabetes/hyperglycemia (PP1_Strong; internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.956, 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 phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (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.