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.673G>C

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA367401125

2691832 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 7b1e5910-73fc-4465-bcee-10f3ce0687bb

Approved on: 2024-02-02

Published on: 2024-02-02

HGVS expressions

NM_033508.3:c.673G>C

NC_000007.14:g.44149763C>G

CM000669.2:g.44149763C>G

NC_000007.13:g.44189362C>G

CM000669.1:g.44189362C>G

NC_000007.12:g.44155887C>G

NG_008847.1:g.44661G>C

NG_008847.2:g.53408G>C

ENST00000395796.8:c.*674G>C

ENST00000616242.5:c.676G>C

ENST00000682635.1:n.1162G>C

ENST00000345378.7:c.679G>C

ENST00000403799.8:c.676G>C

ENST00000671824.1:c.676G>C

ENST00000673284.1:c.676G>C

ENST00000345378.6:c.679G>C

ENST00000395796.7:c.673G>C

ENST00000403799.7:c.676G>C

ENST00000437084.1:c.625G>C

ENST00000616242.4:c.673G>C

NM_000162.3:c.676G>C

NM_033507.1:c.679G>C

NM_033508.1:c.673G>C

NM_000162.4:c.676G>C

NM_001354800.1:c.676G>C

NM_033507.2:c.679G>C

NM_033508.2:c.673G>C

NM_000162.5:c.676G>C

NM_033507.3:c.679G>C

Uncertain Significance

PP2 PM1 PM5_Supporting PM2_Supporting

PP3 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 1.3.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.676G>C variant in the glucokinase gene, GCK, causes an amino acid change of valine to leucine at codon 226 (p.(Val226leu)) of NM_000162.5. This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). 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 (PM2_Supporting). Another missense variant, c.676G>A p.Val226Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Val226Leu (PM5_Supporting). This variant has a REVEL score of 0.667 which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function. This variant was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 21348868). In summary, c.676G>C meets the criteria to be classified as a variant of uncertain signficance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM1, PP2, PM2_Supporting, PM5_Supporting.

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).

PM1

This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1).

PM5_Supporting

Another missense variant, c.676G>A p.Val226Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Val226Leu (PM5_Supporting).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

PP3

This variant has a REVEL score of 0.667 which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function.

PP4

This variant was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 21348868).

Curation History

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