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.463C>G

CA367401894

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 3d39bc92-9cee-422a-ad31-6ddf907d4743

Approved on: 2024-04-28

Published on: 2024-04-28

HGVS expressions

NM_033508.3:c.463C>G

NC_000007.14:g.44150973G>C

CM000669.2:g.44150973G>C

NC_000007.13:g.44190572G>C

CM000669.1:g.44190572G>C

NC_000007.12:g.44157097G>C

NG_008847.1:g.43451C>G

NG_008847.2:g.52198C>G

ENST00000395796.8:c.*464C>G

ENST00000616242.5:c.466C>G

ENST00000682635.1:n.952C>G

ENST00000345378.7:c.469C>G

ENST00000403799.8:c.466C>G

ENST00000671824.1:c.466C>G

ENST00000673284.1:c.466C>G

ENST00000345378.6:c.469C>G

ENST00000395796.7:c.463C>G

ENST00000403799.7:c.466C>G

ENST00000437084.1:c.415C>G

ENST00000616242.4:c.463C>G

NM_000162.3:c.466C>G

NM_033507.1:c.469C>G

NM_033508.1:c.463C>G

NM_000162.4:c.466C>G

NM_001354800.1:c.466C>G

NM_033507.2:c.469C>G

NM_033508.2:c.463C>G

NM_000162.5:c.466C>G

NM_033507.3:c.469C>G

Uncertain Significance

PP3 PP2 PP4 PM5_Supporting 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.466C>G variant in the glucokinase gene, GCK, causes an amino acid change of histidine to aspartate at codon 156 (p.(His156Asp)) 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 0.836, 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 clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). Another missense variant, c.466C>T p.His156Tyr, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.466C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP3, PP2, PM5_Supporting, PP4.

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.836, 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).

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%) (PP4; internal lab contributors).

PM5_Supporting

Another missense variant, c.466C>T p.His156Tyr, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting).

PM2_Supporting

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

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