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.1007A>C

CA367399714

3602116 (ClinVar)

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: a0bc2ca7-34c3-45dd-939a-f747245041ac

Approved on: 2026-08-17

Published on: 2026-09-01

HGVS expressions

NM_033508.3:c.1007A>C

NC_000007.14:g.44146472T>G

CM000669.2:g.44146472T>G

NC_000007.13:g.44186071T>G

CM000669.1:g.44186071T>G

NC_000007.12:g.44152596T>G

NG_008847.1:g.47952A>C

NG_008847.2:g.56699A>C

ENST00000395796.8:c.*1008A>C

ENST00000616242.5:c.*130A>C

ENST00000683378.1:n.236A>C

ENST00000345378.7:c.1013A>C

ENST00000403799.8:c.1010A>C

ENST00000671824.1:c.1073A>C

ENST00000673284.1:c.1010A>C

ENST00000345378.6:c.1013A>C

ENST00000395796.7:c.1007A>C

ENST00000403799.7:c.1010A>C

ENST00000437084.1:c.959A>C

ENST00000473353.1:n.308A>C

ENST00000616242.4:c.1007A>C

NM_000162.3:c.1010A>C

NM_033507.1:c.1013A>C

NM_033508.1:c.1007A>C

NM_000162.4:c.1010A>C

NM_001354800.1:c.1010A>C

NM_001354801.1:c.8+147A>C

NM_033507.2:c.1013A>C

NM_033508.2:c.1007A>C

NM_000162.5:c.1010A>C

NM_033507.3:c.1013A>C

Pathogenic

PS4 PP1 PP3 PP2 PP4_Moderate PM2_Supporting

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1010A>C variant in the glucokinase gene, GCK, causes an amino acid change of glutamine to proline at codon 337 (p.(Gln337Pro)) 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 absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.914, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in ten unrelated individuals with hyperglycemia (PS4; PMIDs: 24918535, 36257325, 19790256, and internal lab contributors). Furthermore, 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 two families (PP1; PMID: 36257325, internal lab contributors). In summary, c.1010A>C 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, approved 10/10/2025): PS4, PP4_Moderate, PM2_Supporting, PP1, PP2, PP3.

PS4

This variant was identified in ten unrelated individuals with hyperglycemia (PS4; PMIDs: 24918535, 36257325, 19790256, and internal lab contributors).

PP1

This variant segregated with diabetes with two informative meioses in two families (PP1; PMID: 36257325, internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.914, 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 v2.1.1 and v4.1 (PM2_Supporting).

PM1

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

Curation History

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