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.1146C>A (p.Cys382Ter)

CA367398741

804835 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: da776d22-419d-4a6d-9750-98caba5a6b45

HGVS expressions

NM_000162.5:c.1146C>A

NM_000162.5(GCK):c.1146C>A (p.Cys382Ter)

NC_000007.14:g.44145604G>T

CM000669.2:g.44145604G>T

NC_000007.13:g.44185203G>T

CM000669.1:g.44185203G>T

NC_000007.12:g.44151728G>T

NG_008847.1:g.48820C>A

NG_008847.2:g.57567C>A

ENST00000395796.8:c.*1144C>A

ENST00000616242.5:c.*266C>A

ENST00000683378.1:n.372C>A

ENST00000336642.9:c.180C>A

ENST00000345378.7:c.1149C>A

ENST00000403799.8:c.1146C>A

ENST00000671824.1:c.1209C>A

ENST00000672743.1:n.158C>A

ENST00000673284.1:c.1146C>A

ENST00000336642.8:n.198C>A

ENST00000345378.6:c.1149C>A

ENST00000395796.7:c.1143C>A

ENST00000403799.7:c.1146C>A

ENST00000437084.1:c.1095C>A

ENST00000459642.1:n.526C>A

ENST00000616242.4:n.1143C>A

NM_000162.3:c.1146C>A

NM_033507.1:c.1149C>A

NM_033508.1:c.1143C>A

NM_000162.4:c.1146C>A

NM_001354800.1:c.1146C>A

NM_001354801.1:c.135C>A

NM_001354802.1:c.6C>A

NM_001354803.1:c.180C>A

NM_033507.2:c.1149C>A

NM_033508.2:c.1143C>A

NM_033507.3:c.1149C>A

NM_033508.3:c.1143C>A

NM_001354803.2:c.180C>A

Pathogenic

PP4 PVS1 PM2_Supporting PS4_Moderate

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 1.2.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1146C>A variant in the glucokinase gene, GCK, results in a premature termination at codon 382 (p.(Cys382Ter)) of NM_000162.5. This variant, located in biologically-relevant exon 9 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). 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 contributors). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors). In summary, c.1146C>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_supporting, PP4, PS4_Moderate.

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% and negative antibodies) (PP4_Moderate; internal lab contributors).

PVS1

This variant, located in biologically-relevant exon 9 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256).

PM2_Supporting

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

PS4_Moderate

This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors).

Approved on: 2023-07-30

Published on: 2023-07-30

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.