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.113A>C (p.Gln38Pro)

CA16618475

420070 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 48a7d27c-294c-4c83-89df-d899b89e63fe

HGVS expressions

NM_000162.5:c.113A>C

NM_000162.5(GCK):c.113A>C (p.Gln38Pro)

NC_000007.14:g.44153396T>G

CM000669.2:g.44153396T>G

NC_000007.13:g.44192995T>G

CM000669.1:g.44192995T>G

NC_000007.12:g.44159520T>G

NG_008847.1:g.41028A>C

NG_008847.2:g.49775A>C

ENST00000395796.8:c.*111A>C

ENST00000616242.5:c.113A>C

ENST00000682635.1:n.599A>C

ENST00000345378.7:c.116A>C

ENST00000403799.8:c.113A>C

ENST00000671824.1:c.113A>C

ENST00000673284.1:c.113A>C

ENST00000345378.6:c.116A>C

ENST00000395796.7:c.110A>C

ENST00000403799.7:c.113A>C

ENST00000437084.1:c.113A>C

ENST00000476008.1:n.548A>C

ENST00000616242.4:c.110A>C

NM_000162.3:c.113A>C

NM_033507.1:c.116A>C

NM_033508.1:c.110A>C

NM_000162.4:c.113A>C

NM_001354800.1:c.113A>C

NM_033507.2:c.116A>C

NM_033508.2:c.110A>C

NM_033507.3:c.116A>C

NM_033508.3:c.110A>C

Pathogenic

PM2_Supporting PP4_Moderate PP1_Strong PP3 PP2 PS4

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.113A>C variant in the glucokinase gene, GCK, causes an amino acid change of glutamine to proline at codon 38 (p.(Gln38Pro)) 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 0.887, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMID: 1508276, 11079754, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT 2 hour glucose < 3 mmol/L)(PP4_Moderate; internal lab contributor). This variant segregated with diabetes/hyperglycemia, with 4 informative meioses in 3 families (PP1_Strong; PMID: 11508276, internal lab contributors). In summary, c.113A>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PS4, PP4_Moderate, PP2, PP3, PM2_Supporting.

PM2_Supporting

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

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 OGTT 2 hour glucose < 3 mmol/L)(PP4_Moderate; internal lab contributor).

PP1_Strong

This variant segregated with diabetes/hyperglycemia, with 4 informative meioses in 3 families (PP1_Strong; PMID: 11508276, internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.887, 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 7 unrelated individuals with hyperglycemia (PS4; PMID: 11508276, 11079754, internal lab contributors).

Approved on: 2024-03-19

Published on: 2024-03-19

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