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.1156C>G (p.Leu386Val)

CA367398705

804837 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 9fe505f4-9287-4671-ac7c-48bfe0745003

HGVS expressions

NM_000162.5:c.1156C>G

NM_000162.5(GCK):c.1156C>G (p.Leu386Val)

NC_000007.14:g.44145594G>C

CM000669.2:g.44145594G>C

NC_000007.13:g.44185193G>C

CM000669.1:g.44185193G>C

NC_000007.12:g.44151718G>C

NG_008847.1:g.48830C>G

NG_008847.2:g.57577C>G

ENST00000395796.8:c.*1154C>G

ENST00000616242.5:c.*276C>G

ENST00000683378.1:n.382C>G

ENST00000336642.9:c.190C>G

ENST00000345378.7:c.1159C>G

ENST00000403799.8:c.1156C>G

ENST00000671824.1:c.1219C>G

ENST00000672743.1:n.168C>G

ENST00000673284.1:c.1156C>G

ENST00000336642.8:c.208C>G

ENST00000345378.6:c.1159C>G

ENST00000395796.7:c.1153C>G

ENST00000403799.7:c.1156C>G

ENST00000437084.1:c.1105C>G

ENST00000459642.1:n.536C>G

ENST00000616242.4:c.1153C>G

NM_000162.3:c.1156C>G

NM_033507.1:c.1159C>G

NM_033508.1:c.1153C>G

NM_000162.4:c.1156C>G

NM_001354800.1:c.1156C>G

NM_001354801.1:c.145C>G

NM_001354802.1:c.16C>G

NM_001354803.1:c.190C>G

NM_033507.2:c.1159C>G

NM_033508.2:c.1153C>G

NM_033507.3:c.1159C>G

NM_033508.3:c.1153C>G

NM_001354803.2:c.190C>G

Pathogenic

PS4 PP1_Strong PM2_Supporting PP3 PP2

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.1156C>G variant in the glucokinase gene, GCK, causes an amino acid change of leucine to valine at codon 386 (p.(Leu386Val)) 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 0.745, 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 at least 13 unrelated individuals with hyperglycemia (PS4; PMID: 19790256, internal lab contributors). This variant segregated with hyperglycemia, with at least 5 informative meioses in multiple families (PP1_Strong; internal lab contributors). In summary, c.1156C>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PS4, PP2, PP3, PM2_Supporting.

PS4

This variant was identified in at least 13 unrelated individuals with hyperglycemia (PS4; PMID: 19790256, internal lab contributors).

PP1_Strong

This variant segregated with hyperglycemia, with at least 5 informative meioses in multiple families (PP1_Strong; internal lab contributors).

PM2_Supporting

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

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.745, 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).

Approved on: 2024-04-28

Published on: 2024-04-28

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