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_033508.3:c.973A>C

CA367399833

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 54f7636b-7d34-417d-86d3-149d6f4ad9d3

Approved on: 2023-12-02

Published on: 2023-12-02

HGVS expressions

NM_033508.3:c.973A>C

NC_000007.14:g.44146506T>G

CM000669.2:g.44146506T>G

NC_000007.13:g.44186105T>G

CM000669.1:g.44186105T>G

NC_000007.12:g.44152630T>G

NG_008847.1:g.47918A>C

NG_008847.2:g.56665A>C

ENST00000395796.8:c.*974A>C

ENST00000616242.5:c.*96A>C

ENST00000683378.1:n.202A>C

ENST00000345378.7:c.979A>C

ENST00000403799.8:c.976A>C

ENST00000671824.1:c.1039A>C

ENST00000673284.1:c.976A>C

ENST00000345378.6:c.979A>C

ENST00000395796.7:c.973A>C

ENST00000403799.7:c.976A>C

ENST00000437084.1:c.925A>C

ENST00000473353.1:n.274A>C

ENST00000616242.4:c.973A>C

NM_000162.3:c.976A>C

NM_033507.1:c.979A>C

NM_033508.1:c.973A>C

NM_000162.4:c.976A>C

NM_001354800.1:c.976A>C

NM_001354801.1:c.8+113A>C

NM_033507.2:c.979A>C

NM_033508.2:c.973A>C

NM_000162.5:c.976A>C

NM_033507.3:c.979A>C

Pathogenic

PS4_Moderate PP3 PP2 PM2_Supporting PP4_Moderate PP1_Strong

PM1

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 1.3.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.976A>C variant in the glucokinase gene, GCK, causes an amino acid change of threonine to proline at codon 326 (p.(Thr326Pro)) of NM_000162.5. 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 is predicted to be deleterious by computational evidence, with a REVEL score of 0.822, 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 four unrelated individuals with hyperglycemia (PMID: 19564454, 31595705, internal lab contributors). One 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 negative antibodies) (PP4_Moderate, internal lab contributor). This variant segregated with hyperglycemia, with six informative meioses in three families (PP1_Strong; internal lab contributors, PMID: 31595705). In summary, c.976A>C 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, approved 8/11/2023): PP4_Moderate, PP1_Strong, PP2, PP3, PM2_Supporting, PS4_Moderate.

PS4_Moderate

This variant was identified in four unrelated individuals with hyperglycemia (PMID: 19564454, 31595705, internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.822, 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).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_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 negative antibodies) (PP4_Moderate, internal lab contributor).

PP1_Strong

This variant segregated with hyperglycemia, with 6 informative meioses in 3 families (PP1_Strong; internal lab contributors).

PM1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

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.