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.122T>C (p.Met41Thr)

CA16609270

393454 (ClinVar)

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: bb7a1a17-a892-4370-aed1-902c1a9bf41d

Approved on: 2026-09-21

Published on: 2026-09-29

HGVS expressions

NM_000162.5(GCK):c.122T>C (p.Met41Thr)

NM_000162.5:c.122T>C

NC_000007.14:g.44153387A>G

CM000669.2:g.44153387A>G

NC_000007.13:g.44192986A>G

CM000669.1:g.44192986A>G

NC_000007.12:g.44159511A>G

NG_008847.1:g.41037T>C

NG_008847.2:g.49784T>C

ENST00000395796.8:c.*120T>C

ENST00000616242.5:c.122T>C

ENST00000682635.1:n.608T>C

ENST00000345378.7:c.125T>C

ENST00000403799.8:c.122T>C

ENST00000671824.1:c.122T>C

ENST00000673284.1:c.122T>C

ENST00000345378.6:c.125T>C

ENST00000395796.7:c.119T>C

ENST00000403799.7:c.122T>C

ENST00000437084.1:c.122T>C

ENST00000616242.4:c.119T>C

NM_000162.3:c.122T>C

NM_033507.1:c.125T>C

NM_033508.1:c.119T>C

NM_000162.4:c.122T>C

NM_001354800.1:c.122T>C

NM_033507.2:c.125T>C

NM_033508.2:c.119T>C

NM_033507.3:c.125T>C

NM_033508.3:c.119T>C

Pathogenic

PP1_Strong PP4_Moderate PP3 PP2 PS4 PM2_Supporting

BP4 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.122T>C variant in the glucokinase, GCK, causes an amino acid change of methionine to threonine at codon 41 (p.Met41Thr) 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 0.979 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 at least eight individuals with hyperglycemia (PS4; PMID: 29510678; 34746319, internal lab contributors). Additionally, at least one of these individuals had a clinical history highly specific for GCK-hyperglycemia (pediatric case withfasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative autoantibodies) (PP4_Moderate; PMID: 29510678). This variant segregated with hyperglycemia with six informative meioses in four families (PP1_Strong; PMID: 29510678, 34746319, internal lab contributors). In summary, c.122T>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, PP1_Strong, PM2_Supporting, PP4_Moderate, PP3, PP2.

PP1_Strong

This variant segregated with hyperglycemia with six informative meioses in four families (PP1_Strong; PMID: 29510678, 34746319, internal lab contributors)

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 autoantibodies) (PP4_Moderate; PMID: 29510678).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.979 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 at least eight individuals with hyperglycemia (PS4; PMID: 29510678; 34746319, internal lab contributors).

PM2_Supporting

Absent from gnomAD v4.1.1 (PM2_Supporting).

BP4

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

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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