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>A (p.Val33Glu)

CA367403606

435309 (ClinVar)

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: 3f0283f1-d408-433d-a871-21918fd3bf85

Approved on: 2026-04-17

Published on: 2026-06-24

HGVS expressions

NM_000162.5(GCK):c.98T>A (p.Val33Glu)

NM_000162.5:c.98T>A

NC_000007.14:g.44153411A>T

CM000669.2:g.44153411A>T

NC_000007.13:g.44193010A>T

CM000669.1:g.44193010A>T

NC_000007.12:g.44159535A>T

NG_008847.1:g.41013T>A

NG_008847.2:g.49760T>A

ENST00000395796.8:c.*96T>A

ENST00000616242.5:c.98T>A

ENST00000682635.1:n.584T>A

ENST00000345378.7:c.101T>A

ENST00000403799.8:c.98T>A

ENST00000671824.1:c.98T>A

ENST00000673284.1:c.98T>A

ENST00000345378.6:c.101T>A

ENST00000395796.7:c.95T>A

ENST00000403799.7:c.98T>A

ENST00000437084.1:c.98T>A

ENST00000476008.1:n.533T>A

ENST00000616242.4:c.95T>A

NM_000162.3:c.98T>A

NM_033507.1:c.101T>A

NM_033508.1:c.95T>A

NM_000162.4:c.98T>A

NM_001354800.1:c.98T>A

NM_033507.2:c.101T>A

NM_033508.2:c.95T>A

NM_033507.3:c.101T>A

NM_033508.3:c.95T>A

Uncertain Significance

PM2_Supporting PM5_Supporting PP3 PP2

PS4 PP4

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 3.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.98T>A variant in the glucokinase gene, GCK, causes an amnio acid change of valine to glutamate at codon 33 (p.(Val33Glu)) of NM_000162.5. 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 0.97, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant at the same residue, c.98T>C (p.Val33Ala), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar, internal lab contributors). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.98T>A meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.1.0, approved 10/10/2025): PM2_Supporting, PP2, PP3, PM5_supporting.

PM2_Supporting

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

PM5_Supporting

Another missense variant at the same residue, c.98T>C (p.Val33Ala), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.97, 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 two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar, internal lab contributors).

PP4

This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors).

Curation History

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