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_000162.5(GCK):c.533G>A (p.Gly178Glu)

CA10588428

265174 (ClinVar)

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: 58340443-0eda-4023-b399-6eb7a888346b

Approved on: 2025-11-24

Published on: 2025-11-26

HGVS expressions

NM_000162.5:c.533G>A

NM_000162.5(GCK):c.533G>A (p.Gly178Glu)

NC_000007.14:g.44150015C>T

CM000669.2:g.44150015C>T

NC_000007.13:g.44189614C>T

CM000669.1:g.44189614C>T

NC_000007.12:g.44156139C>T

NG_008847.1:g.44409G>A

NG_008847.2:g.53156G>A

ENST00000395796.8:c.*531G>A

ENST00000616242.5:c.533G>A

ENST00000682635.1:n.1019G>A

ENST00000345378.7:c.536G>A

ENST00000403799.8:c.533G>A

ENST00000671824.1:c.533G>A

ENST00000673284.1:c.533G>A

ENST00000345378.6:c.536G>A

ENST00000395796.7:c.530G>A

ENST00000403799.7:c.533G>A

ENST00000437084.1:c.482G>A

ENST00000616242.4:c.530G>A

NM_000162.3:c.533G>A

NM_033507.1:c.536G>A

NM_033508.1:c.530G>A

NM_000162.4:c.533G>A

NM_001354800.1:c.533G>A

NM_033507.2:c.536G>A

NM_033508.2:c.530G>A

NM_033507.3:c.536G>A

NM_033508.3:c.530G>A

Pathogenic

PP4_Moderate PP1_Strong PM2_Supporting PS4 PP3 PP2

PM1

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 3.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.533G>A variant in the glucokinase gene, GCK, causes an amnio acid change of glycine to glutamic acid at codon 178 (p.(Gly178Glu)) of NM_000162.5. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 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 0.964, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 20 unrelated individuals with hyperglycemia (PMID: 25555642, 15928245, 30259503, 34556497, 29056535, 38054414, 19564454, 36257325, internal lab contributors) (PS4). This variant was identified in multiple individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia, with at least 11 informative meioses in six families (PP1_Strong; PMID: 34556497, 36257325; internal lab contributors). In summary, c.533G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.1.0, approved 10/10/2025): PS4, PM2_Supporting, PP2, PP3, PP4_Moderate, PP1_Strong

PP4_Moderate

This variant was identified in multiple individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; Internal lab contributors)

PP1_Strong

This variant segregated with hyperglycemia, with at least 11 informative meioses in six families (PP1_Strong; PMID: 34556497, 36257325; Internal lab contributors ).

PM2_Supporting

This variant is absent in gnomAD v2.1 and v4.1.

PS4

This variant was identified in at least 20 unrelated individuals with hyperglycemia (PS4 PMIDs: 36257325, 34556497, 30259503, 29056535; ClinVar, internal lab contributors]).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.964, 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).

PM1

This variant does not reside in an amino acid that directly binds glucose or ATP, which are defined as critical for the GCK protein's function by the ClinGen MDEP.

Curation History

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