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.530G>C

CA367401650

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: 1ef25737-db66-4cad-8e09-5c46e6dfc8d4

Approved on: 2025-11-26

Published on: 2025-11-26

HGVS expressions

NM_033508.3:c.530G>C

NC_000007.14:g.44150015C>G

CM000669.2:g.44150015C>G

NC_000007.13:g.44189614C>G

CM000669.1:g.44189614C>G

NC_000007.12:g.44156139C>G

NG_008847.1:g.44409G>C

NG_008847.2:g.53156G>C

ENST00000395796.8:c.*531G>C

ENST00000616242.5:c.533G>C

ENST00000682635.1:n.1019G>C

ENST00000345378.7:c.536G>C

ENST00000403799.8:c.533G>C

ENST00000671824.1:c.533G>C

ENST00000673284.1:c.533G>C

ENST00000345378.6:c.536G>C

ENST00000395796.7:c.530G>C

ENST00000403799.7:c.533G>C

ENST00000437084.1:c.482G>C

ENST00000616242.4:c.530G>C

NM_000162.3:c.533G>C

NM_033507.1:c.536G>C

NM_033508.1:c.530G>C

NM_000162.4:c.533G>C

NM_001354800.1:c.533G>C

NM_033507.2:c.536G>C

NM_033508.2:c.530G>C

NM_000162.5:c.533G>C

NM_033507.3:c.536G>C

Likely Pathogenic

PM2_Supporting PM5_Supporting PP4_Moderate PP1 PP3 PP2

PS4 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>C variant in the glucokinase gene, GCK, causes an amnio acid change of glycine to alanine at codon 178 (p.(Gly178Ala)) 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 0.954, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1 and v4.1 (PM2_Supporting). This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 36257325, 29412391, 36504295). One of these individuals did have 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; PMID:29412391). Additionally, this variant segregated with hyperglycemia, with 3 informative meioses in a single family (PP1; PMID: 29412391, 28012402). Another missense variant at the same residue, c.533G>A p.Gly178Glu, has been interpreted as pathogenic by the ClinGen MDEP, but has a greater Grantham distance than p.Gly178Ala (PM5_Supporting). In summary, c.533G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.1.0, approved 10/10/2025): PP1, PM2_Supporting, PM5_Supporting, PP2, PP3, PP4_Moderate

PM2_Supporting

This variant is absent in gnomAD v2.1 and v4.1 (PM2_Supporting).

PM5_Supporting

Another missense variant, c.533G>A p.Gly178Glu, has been interpreted as pathogenic by the ClinGen MDEP,, but has a greater Grantham distance than p.Gly178Ala (PM5_Supporting).

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% and negative antibodies) (PP4_Moderate; PMID:29412391)

PP1

This variant segregated with hyperglycemia, with 3 informative meioses in a single family (PP1; PMID: 29412391, 28012402)

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.954, 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).

PS4

This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 36257325, 29412391, 36504295).

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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