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.566T>C (p.Ile189Thr)

CA367401550

431972 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 7e0e63cf-14f1-40ba-9af0-8f9179fc282a

Approved on: 2023-05-08

Published on: 2023-05-08

HGVS expressions

NM_000162.5:c.566T>C

NM_000162.5(GCK):c.566T>C (p.Ile189Thr)

NC_000007.14:g.44149982A>G

CM000669.2:g.44149982A>G

NC_000007.13:g.44189581A>G

CM000669.1:g.44189581A>G

NC_000007.12:g.44156106A>G

NG_008847.1:g.44442T>C

NG_008847.2:g.53189T>C

ENST00000395796.8:c.*564T>C

ENST00000616242.5:c.566T>C

ENST00000682635.1:n.1052T>C

ENST00000345378.7:c.569T>C

ENST00000403799.8:c.566T>C

ENST00000671824.1:c.566T>C

ENST00000673284.1:c.566T>C

ENST00000345378.6:c.569T>C

ENST00000395796.7:c.563T>C

ENST00000403799.7:c.566T>C

ENST00000437084.1:c.515T>C

ENST00000616242.4:n.563T>C

NM_000162.3:c.566T>C

NM_033507.1:c.569T>C

NM_033508.1:c.563T>C

NM_000162.4:c.566T>C

NM_001354800.1:c.566T>C

NM_033507.2:c.569T>C

NM_033508.2:c.563T>C

NM_033507.3:c.569T>C

NM_033508.3:c.563T>C

Pathogenic

PM2_Supporting PP1_Strong PS4 PP4 PP3 PP2

PM1

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.566T>C variant in the glucokinase gene, GCK, causes an amino acid change of isoleucine to threonine at codon 189 (p.Ile189Thr) of NM_000162.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.969, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (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 was identified in 7 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors). Additionally, this variant was identified in at least one individual with a clinical history highly specific for GCK-MODY (fasting glucose = 125 mg/dl and HbA1c = 6.5%) (PP4, internal lab contributors). Lastly, this variant segregated with diabetes, with five informative meioses in two families with MODY (PP1_Strong; internal lab contributors). In summary, c.566T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1.0, approved 3/23/2023): PM2_Supporting, PP3, PP2, PP4, PP1_Strong, PS4.

PM2_Supporting

Absent from gnomAD

PP1_Strong

5 meioses in 2 families (internal lab contributors)

PS4

7 unrelated cases from internal lab contributors

PP4

Identified in a patient with fasting glucose of 125 mg/dl and HbA1c = 6.5% (internal laboratory collaborators).

PP3

REVEL = 0.969

PP2

Missense variant in GCK

PM1

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

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