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]

Variant: NM_033508.3:c.520G>C

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA367401686

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: ec7b2d5a-610b-414c-b06f-1491afbeff7c

Approved on: 2024-02-23

Published on: 2024-02-23

HGVS expressions

NM_033508.3:c.520G>C

NC_000007.14:g.44150025C>G

CM000669.2:g.44150025C>G

NC_000007.13:g.44189624C>G

CM000669.1:g.44189624C>G

NC_000007.12:g.44156149C>G

NG_008847.1:g.44399G>C

NG_008847.2:g.53146G>C

ENST00000395796.8:c.*521G>C

ENST00000616242.5:c.523G>C

ENST00000682635.1:n.1009G>C

ENST00000345378.7:c.526G>C

ENST00000403799.8:c.523G>C

ENST00000671824.1:c.523G>C

ENST00000673284.1:c.523G>C

ENST00000345378.6:c.526G>C

ENST00000395796.7:c.520G>C

ENST00000403799.7:c.523G>C

ENST00000437084.1:c.472G>C

ENST00000616242.4:c.520G>C

NM_000162.3:c.523G>C

NM_033507.1:c.526G>C

NM_033508.1:c.520G>C

NM_000162.4:c.523G>C

NM_001354800.1:c.523G>C

NM_033507.2:c.526G>C

NM_033508.2:c.520G>C

NM_000162.5:c.523G>C

NM_033507.3:c.526G>C

Pathogenic

PP1_Strong PS4 PS1 PP4_Moderate PP3 PP2 PM2_Supporting

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.523G>C variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 175 (p.(Gly175Arg)) 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 0.965, 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 five unrelated individuals with hyperglycemia (PS4_Moderate; PMIDs:21978167, internal lab contributors). This variant segregated with diabetes/hyperglycemia, with at least six informative meioses in two families (PP1_Strong; 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%, antibody negative and three-generation, dominant family history of diabetes or hyperglycemia in a family not used for PP1) (PP4_Moderate; PMIDs:21978167). The nucleotide change c.523G>A, which causes the same amino acid change, has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP (PS1). In summary, c.523G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PP4_Moderate, PS4_Moderate, PM2_Supporting, PP2, PP3, PS1.

PP1_Strong

This variant segregated with diabetes/hyperglycemia, with at least six informative meioses in two families (PP1_Strong; internal lab contributors).

PS4

This variant was identified in five unrelated individuals with hyperglycemia (PS4_Moderate; PMIDs:21978167, internal lab contributors).

PS1

The nucleotide change c.523G>A, which causes the same amino acid change, has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP (PS1).

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%, antibody negative and three-generation, dominant family history of diabetes or hyperglycemia in a family not used for PP1) (PP4_Moderate; PMIDs:21978167).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.965, 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).

Curation History

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