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.406C>G

CA367402081

3893273 (ClinVar)

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: 729e8fd5-33e3-4362-b6d7-552d13f35b31

Approved on: 2025-04-17

Published on: 2025-04-17

HGVS expressions

NM_033508.3:c.406C>G

NC_000007.14:g.44151030G>C

CM000669.2:g.44151030G>C

NC_000007.13:g.44190629G>C

CM000669.1:g.44190629G>C

NC_000007.12:g.44157154G>C

NG_008847.1:g.43394C>G

NG_008847.2:g.52141C>G

ENST00000395796.8:c.*407C>G

ENST00000616242.5:c.409C>G

ENST00000682635.1:n.895C>G

ENST00000345378.7:c.412C>G

ENST00000403799.8:c.409C>G

ENST00000671824.1:c.409C>G

ENST00000673284.1:c.409C>G

ENST00000345378.6:c.412C>G

ENST00000395796.7:c.406C>G

ENST00000403799.7:c.409C>G

ENST00000437084.1:c.364-6C>G

ENST00000616242.4:c.406C>G

NM_000162.3:c.409C>G

NM_033507.1:c.412C>G

NM_033508.1:c.406C>G

NM_000162.4:c.409C>G

NM_001354800.1:c.409C>G

NM_033507.2:c.412C>G

NM_033508.2:c.406C>G

NM_000162.5:c.409C>G

NM_033507.3:c.412C>G

Likely Pathogenic

PS3_Moderate PP1 PP3 PP2 PM5_Supporting PM2_Supporting PP4_Moderate

PS4

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 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.409C>G variant in the glucokinase gene, GCK, causes an amino acid change of histidine to aspartic acid at codon 137 (p.(His137Asp)) 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). The variant is absent in gnomAD v2.1 and v4.1 (PM2_Supporting). It is predicted to be deleterious by computational evidence, with a REVEL score of 0.747, which is greater than the MDEP VCEP threshold of 0.70 (PP3). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.26, which is below the MDEP cutoff (<0.5) (PS3_Moderate, PMID: 22761713). Another missense variant at the same codon, c.410A>G, p.(His137Arg), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). The p.His137Asp 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: 18382660, Internal lab contributors). One of these individuals has 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: 18382660). This variant segregated with hyperglycemia, with 2 informative meioses in 2 families (PP1; PMID: 18382660, internal lab contributors). In summary, c.409C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PS3_Moderate, PP4_Moderate, PM2_supporting, PM5_Supporting, PP1, PP2, PP3.

PS3_Moderate

MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.26, which is below the MDEP cutoff (<0.5) (PMID: 22761713)

PP1

This variant segregated with hyperglycemia, with 2 informative meioses in 2 families (PP1; PMID: 18382660, internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.747, 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).

PM5_Supporting

Another missense variant at the same codon, c.410A>G, p.(His137Arg), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting).

PM2_Supporting

Absent in gnomAD v2.1 and v4.1 (PM2_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: 18382660).

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: 18382660, 36257325, Internal lab contributors).

Curation History

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