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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000162.5(GCK):c.781G>C (p.Gly261Arg)

CA367400571

447418 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: fb522608-bab6-43d3-9eb8-e195b15539cd

HGVS expressions

NM_000162.5:c.781G>C

NM_000162.5(GCK):c.781G>C (p.Gly261Arg)

NC_000007.14:g.44147732C>G

CM000669.2:g.44147732C>G

NC_000007.13:g.44187331C>G

CM000669.1:g.44187331C>G

NC_000007.12:g.44153856C>G

NG_008847.1:g.46692G>C

NG_008847.2:g.55439G>C

ENST00000395796.8:c.*779G>C

ENST00000616242.5:c.781G>C

ENST00000345378.7:c.784G>C

ENST00000403799.8:c.781G>C

ENST00000671824.1:c.781G>C

ENST00000673284.1:c.781G>C

ENST00000345378.6:c.784G>C

ENST00000395796.7:c.778G>C

ENST00000403799.7:c.781G>C

ENST00000437084.1:c.730G>C

ENST00000616242.4:n.778G>C

NM_000162.3:c.781G>C

NM_033507.1:c.784G>C

NM_033508.1:c.778G>C

NM_000162.4:c.781G>C

NM_001354800.1:c.781G>C

NM_033507.2:c.784G>C

NM_033508.2:c.778G>C

NM_033507.3:c.784G>C

NM_033508.3:c.778G>C

Pathogenic

PP4_Moderate PM2_Supporting PS3_Moderate PS4_Moderate PS1 PP3 PP2

PM1 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 1.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.781G>C variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 261 (p.(Gly261Arg)) 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 0.914, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). This variant was identified in 5 unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors). The nucleotide change c.781G>A, which causes the same amino acid change, has been classified as pathogenic by the ClinGen MDEP (PS1). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Gly261Arg variant has a relative activity index (RAI) of 0.02, which is less than the MDEP VCEP threshold of 0.50 (PMID: 19903754). In summary, the c.781G>C variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PS3_Moderate, PS1, PS4_Moderate, PP4_Moderate.

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors).

PM2_Supporting

This variant has an incomputable gnomAD v2.1.1 Popmax minor filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the "Other" subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting).

PS3_Moderate

A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Gly261Arg variant has a relative activity index (RAI) of 0.02, which is less than the MDEP VCEP threshold of 0.50 (PMID: 19903754).

PS4_Moderate

This variant was identified in 5 unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors).

PS1

The nucleotide change c.781G>A, which causes the same amino acid change, has been classified as pathogenic by the ClinGen MDEP (PS1).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.913, which is greater than the MDEP 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).

PM1

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

PP1

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

Approved on: 2023-08-12

Published on: 2023-08-12

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.