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.98T>C (p.Val33Ala)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA367403604

585930 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 36f8d790-f31d-4409-b22e-8ef6101888b9

Approved on: 2025-06-27

Published on: 2025-06-27

HGVS expressions

NM_000162.5:c.98T>C

NM_000162.5(GCK):c.98T>C (p.Val33Ala)

NC_000007.14:g.44153411A>G

CM000669.2:g.44153411A>G

NC_000007.13:g.44193010A>G

CM000669.1:g.44193010A>G

NC_000007.12:g.44159535A>G

NG_008847.1:g.41013T>C

NG_008847.2:g.49760T>C

ENST00000395796.8:c.*96T>C

ENST00000616242.5:c.98T>C

ENST00000682635.1:n.584T>C

ENST00000345378.7:c.101T>C

ENST00000403799.8:c.98T>C

ENST00000671824.1:c.98T>C

ENST00000673284.1:c.98T>C

ENST00000345378.6:c.101T>C

ENST00000395796.7:c.95T>C

ENST00000403799.7:c.98T>C

ENST00000437084.1:c.98T>C

ENST00000476008.1:n.533T>C

ENST00000616242.4:c.95T>C

NM_000162.3:c.98T>C

NM_033507.1:c.101T>C

NM_033508.1:c.95T>C

NM_000162.4:c.98T>C

NM_001354800.1:c.98T>C

NM_033507.2:c.101T>C

NM_033508.2:c.95T>C

NM_033507.3:c.101T>C

NM_033508.3:c.95T>C

Likely Pathogenic

PM2_Supporting PS4 PP3 PP2 PP4_Moderate

PM5 PM1 PS3

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.98T>C variant in the glucokinase gene, GCK, causes an amnio acid change of valine to alanine at codon 33 (p.(Val33Ala)) of NM_000162.5. This variant was identified in at least 17 unrelated individuals with hyperglycemia (PS4; PMID: 22332836, 26641800, 36257325 internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 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 0.929, which is greater than the MDEP VCEP threshold of 0.70 (PP3). 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 antibody negative (PP4_Moderate; internal lab contributors). The relative activity index (RAI) of this variant was above the MDEP cutoff of 0.5, and thermostability was not evaluated; therefore PS3 was not applied (PMID: 28842611). Additional missense variants at the same codon, c.98T>A p.(Val33Glu) and c.98T>G p.(Val33Gly) have been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.98T>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 2.0.0, approved 2/17/2025): PS4, PM2_Supporting, PP2, PP3, PP4_Moderate.

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

PS4

This variant was identified in at least 17 unrelated individuals with hyperglycemia (PS4; PMID: 22332836 (10), 26641800 (2), 36257325 (1), internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.929, 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 antibody negative (PP4_Moderate; internal lab contributors).

PM5

Additional missense variants, c.98T>A p.(Val33Glu) and c.98T>G p.(Val33Gly) have been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied.

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.

PS3

The relative activity index (RAI) of this variant was above the MDEP cutoff of 0.5, and thermostability was not evaluated; therefore PS3 was not applied (PMID: 28842611).

Curation History

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