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.1139A>C (p.His380Pro)

CA367398780

1098819 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 25b05c55-bdc8-4ab4-827f-8ae499b52ff9

HGVS expressions

NM_000162.5:c.1139A>C

NM_000162.5(GCK):c.1139A>C (p.His380Pro)

NC_000007.14:g.44145611T>G

CM000669.2:g.44145611T>G

NC_000007.13:g.44185210T>G

CM000669.1:g.44185210T>G

NC_000007.12:g.44151735T>G

NG_008847.1:g.48813A>C

NG_008847.2:g.57560A>C

ENST00000395796.8:c.*1137A>C

ENST00000616242.5:c.*259A>C

ENST00000683378.1:n.365A>C

ENST00000336642.9:c.173A>C

ENST00000345378.7:c.1142A>C

ENST00000403799.8:c.1139A>C

ENST00000671824.1:c.1202A>C

ENST00000672743.1:n.151A>C

ENST00000673284.1:c.1139A>C

ENST00000336642.8:c.191A>C

ENST00000345378.6:c.1142A>C

ENST00000395796.7:c.1136A>C

ENST00000403799.7:c.1139A>C

ENST00000437084.1:c.1088A>C

ENST00000459642.1:n.519A>C

ENST00000616242.4:c.1136A>C

NM_000162.3:c.1139A>C

NM_033507.1:c.1142A>C

NM_033508.1:c.1136A>C

NM_000162.4:c.1139A>C

NM_001354800.1:c.1139A>C

NM_001354801.1:c.128A>C

NM_001354802.1:c.-2A>C

NM_001354803.1:c.173A>C

NM_033507.2:c.1142A>C

NM_033508.2:c.1136A>C

NM_033507.3:c.1142A>C

NM_033508.3:c.1136A>C

NM_001354803.2:c.173A>C

Pathogenic

PP4_Moderate PM2_Supporting PP1_Strong PS4 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 1.3.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1139A>C variant in the glucokinase gene, GCK, causes an amino acid change of histidine to proline at codon 380 (p.(His380Pro)) 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 0.789, 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 nine unrelated individuals with hyperglycemia (PS4; PMIDs: 34440516, 19790256, internal lab contributors). At least two 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 2 hour OGTT increment < 3 mmol/L or negative antibodies) (PP4_Moderate, PMID: 34440516, internal lab contributor). This variant segregated with hyperglycemia, with at least eight informative meioses in six families (PP1_Strong; PMID: 34440516, internal lab contributor). In summary, c.1139A>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, approved 8/11/2023): PP4_Moderate, PS4, PP2, PP3, PM2_Supporting, PP1_Strong.

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 2 hour OGTT increment < 3 mmol/L or negative antibodies) (PP4_Moderate, PMID: 34440516; internal lab contributors).

PM2_Supporting

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

PP1_Strong

This variant segregated with hyperglycemia, with at least eight informative meioses in six families (PP1_Strong; PMID: 34440516, internal lab contributor).

PS4

This variant was identified in 9 unrelated individuals with hyperglycemia (PS4; PMIDs: 34440516, 19790256, internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.789, 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).

PM1

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

Approved on: 2023-09-19

Published on: 2023-09-19

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