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]

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Variant: NM_000162.5(GCK):c.524G>T (p.Gly175Val)

CA367401683

1746353 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 49cf4b5c-fb03-4ade-8315-3fb8aa33a104

Approved on: 2024-02-23

Published on: 2024-02-23

HGVS expressions

NM_000162.5:c.524G>T

NM_000162.5(GCK):c.524G>T (p.Gly175Val)

NC_000007.14:g.44150024C>A

CM000669.2:g.44150024C>A

NC_000007.13:g.44189623C>A

CM000669.1:g.44189623C>A

NC_000007.12:g.44156148C>A

NG_008847.1:g.44400G>T

NG_008847.2:g.53147G>T

ENST00000395796.8:c.*522G>T

ENST00000616242.5:c.524G>T

ENST00000682635.1:n.1010G>T

ENST00000345378.7:c.527G>T

ENST00000403799.8:c.524G>T

ENST00000671824.1:c.524G>T

ENST00000673284.1:c.524G>T

ENST00000345378.6:c.527G>T

ENST00000395796.7:c.521G>T

ENST00000403799.7:c.524G>T

ENST00000437084.1:c.473G>T

ENST00000616242.4:c.521G>T

NM_000162.3:c.524G>T

NM_033507.1:c.527G>T

NM_033508.1:c.521G>T

NM_000162.4:c.524G>T

NM_001354800.1:c.524G>T

NM_033507.2:c.527G>T

NM_033508.2:c.521G>T

NM_033507.3:c.527G>T

NM_033508.3:c.521G>T

Uncertain Significance

PM5_Supporting PM2_Supporting PP3 PP2

PP4 PP1

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.524G>T variant in the glucokinase gene, GCK, causes an amino acid change of glycine to valine at codon 175 (p.(Gly175Val)) 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 0.98, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.523G>A p.Gly175Arg, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Gly175Val (PM5_Supporting). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, PMID: 11315851). 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 (PMID:28012402, 11315851, internal lab contributors). In summary, c.524G>T meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PM5_Supporting.

PM5_Supporting

Another missense variant, c.523G>A p.Gly175Arg, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Gly175Val (PM5_Supporting).

PM2_Supporting

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

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.98, 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

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 (PMID:28012402, 11315851, internal lab contributors).

PP1

This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, PMID: 11315851).

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