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.497G>C

CA367401763

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: 3217af19-2337-40f7-b677-acb8e47dd3eb

Approved on: 2026-08-21

Published on: 2026-09-02

HGVS expressions

NM_033508.3:c.497G>C

NC_000007.14:g.44150048C>G

CM000669.2:g.44150048C>G

NC_000007.13:g.44189647C>G

CM000669.1:g.44189647C>G

NC_000007.12:g.44156172C>G

NG_008847.1:g.44376G>C

NG_008847.2:g.53123G>C

ENST00000395796.8:c.*498G>C

ENST00000616242.5:c.500G>C

ENST00000682635.1:n.986G>C

ENST00000345378.7:c.503G>C

ENST00000403799.8:c.500G>C

ENST00000671824.1:c.500G>C

ENST00000673284.1:c.500G>C

ENST00000345378.6:c.503G>C

ENST00000395796.7:c.497G>C

ENST00000403799.7:c.500G>C

ENST00000437084.1:c.449G>C

ENST00000616242.4:c.497G>C

NM_000162.3:c.500G>C

NM_033507.1:c.503G>C

NM_033508.1:c.497G>C

NM_000162.4:c.500G>C

NM_001354800.1:c.500G>C

NM_033507.2:c.503G>C

NM_033508.2:c.497G>C

NM_000162.5:c.500G>C

NM_033507.3:c.503G>C

Likely Pathogenic

PP3 PP2 PP4_Moderate PM2_Supporting PM5_Supporting

PP1 PM1 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 3.1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.500G>C variant in the glucokinase gene, GCK, causes an amino acid change of tryptophan to serine at codon 167 (p.(Trp167Ser)) 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 0.949, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v4.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). At least one of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). Another missense variant at the same residue, c.499T>C (p.Trp167Arg), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.500G>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): PP4_Moderate, PM2_Supporting, PM5_Supporting, PP2, PP3.

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.949, 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_Moderate

This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors).

PM2_Supporting

This variant is absent from gnomAD v4.1.1 (PM2_Supporting).

PM5_Supporting

Another missense variant at the same residue, c.499T>C (p.Trp167Arg), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting).

PP1

This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors).

PM1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS4

This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors).

Curation History

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