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.625A>G

CA367401305

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 86a528ed-c634-4a50-b738-b0dc8e790ff2

HGVS expressions

NM_033508.3:c.625A>G

NC_000007.14:g.44149811T>C

CM000669.2:g.44149811T>C

NC_000007.13:g.44189410T>C

CM000669.1:g.44189410T>C

NC_000007.12:g.44155935T>C

NG_008847.1:g.44613A>G

NG_008847.2:g.53360A>G

ENST00000395796.8:c.*626A>G

ENST00000616242.5:c.628A>G

ENST00000682635.1:n.1114A>G

ENST00000345378.7:c.631A>G

ENST00000403799.8:c.628A>G

ENST00000671824.1:c.628A>G

ENST00000673284.1:c.628A>G

ENST00000345378.6:c.631A>G

ENST00000395796.7:c.625A>G

ENST00000403799.7:c.628A>G

ENST00000437084.1:c.577A>G

ENST00000616242.4:n.625A>G

NM_000162.3:c.628A>G

NM_033507.1:c.631A>G

NM_033508.1:c.625A>G

NM_000162.4:c.628A>G

NM_001354800.1:c.628A>G

NM_033507.2:c.631A>G

NM_033508.2:c.625A>G

NM_000162.5:c.628A>G

NM_033507.3:c.631A>G

Likely Pathogenic

PM2_Supporting PM5_Strong PP4 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 1.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.628A>G variant in the glucokinase gene, GCK causes an amino acid change of methionine to valine at codon 210 (p.(Met210Val)) 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 also predicted to be deleterious by computational evidence, with a REVEL score of 0.952, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributor). Additionally, Two other missense variants, c.629T>A (p.Met210Lys) and c.629T>C (p.Met210Thr), have been classified as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.628A>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP ((specification version 1.1.0, approved 3/23/2023): PM5_Strong, PP2, PP3, PP4, PM2_Supporting.

PM2_Supporting

Absent in gnomAD v2.1.1 (PM2_Supporting).

PM5_Strong

Two other missense variants, c.629T>A (p.Met210Lys) and c.629T>C (p.Met210Thr), have been classified as pathogenic by the ClinGen MDEP (PM5_Strong).

PP4

This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributor).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.952, 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: 2023-05-26

Published on: 2023-05-26

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