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.1174C>G (p.Arg392Gly)

CA367398625

1301416 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: db7bf11d-d41d-4e61-a283-7588f3278993

HGVS expressions

NM_000162.5:c.1174C>G

NM_000162.5(GCK):c.1174C>G (p.Arg392Gly)

NC_000007.14:g.44145576G>C

CM000669.2:g.44145576G>C

NC_000007.13:g.44185175G>C

CM000669.1:g.44185175G>C

NC_000007.12:g.44151700G>C

NG_008847.1:g.48848C>G

NG_008847.2:g.57595C>G

ENST00000395796.8:c.*1172C>G

ENST00000616242.5:c.*294C>G

ENST00000683378.1:n.400C>G

ENST00000336642.9:c.208C>G

ENST00000345378.7:c.1177C>G

ENST00000403799.8:c.1174C>G

ENST00000671824.1:c.1237C>G

ENST00000672743.1:n.186C>G

ENST00000673284.1:c.1174C>G

ENST00000336642.8:n.226C>G

ENST00000345378.6:c.1177C>G

ENST00000395796.7:c.1171C>G

ENST00000403799.7:c.1174C>G

ENST00000437084.1:c.1123C>G

ENST00000459642.1:n.554C>G

ENST00000616242.4:n.1171C>G

NM_000162.3:c.1174C>G

NM_033507.1:c.1177C>G

NM_033508.1:c.1171C>G

NM_000162.4:c.1174C>G

NM_001354800.1:c.1174C>G

NM_001354801.1:c.163C>G

NM_001354802.1:c.34C>G

NM_001354803.1:c.208C>G

NM_033507.2:c.1177C>G

NM_033508.2:c.1171C>G

NM_033507.3:c.1177C>G

NM_033508.3:c.1171C>G

NM_001354803.2:c.208C>G

Uncertain Significance

PM2 PM5_Supporting 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 1.2.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1174C>G variant in the glucokinase gene, GCK, causes an amino acid change of arginine to glycine at codon 392 (p.(Arg392Gly)) 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 0.93 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 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.1174C>T p.Arg392Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg392Gly (PM5_Supporting). In summary, c.1174C>G meets the criteria to be classified as a VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PM5_Supporting.

PM2

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

PM5_Supporting

Another missense variant, c.1174C>T p.Arg392Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg392Gly (PM5_Supporting).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.93 which is greater than or equal to 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: 2023-08-26

Published on: 2023-08-26

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