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.1157T>C (p.Leu386Pro)

CA213723

36180 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: c4a62d4d-a903-4909-823c-f2774bc16754

HGVS expressions

NM_000162.5:c.1157T>C

NM_000162.5(GCK):c.1157T>C (p.Leu386Pro)

NC_000007.14:g.44145593A>G

CM000669.2:g.44145593A>G

NC_000007.13:g.44185192A>G

CM000669.1:g.44185192A>G

NC_000007.12:g.44151717A>G

NG_008847.1:g.48831T>C

NG_008847.2:g.57578T>C

ENST00000395796.8:c.*1155T>C

ENST00000616242.5:c.*277T>C

ENST00000683378.1:n.383T>C

ENST00000336642.9:c.191T>C

ENST00000345378.7:c.1160T>C

ENST00000403799.8:c.1157T>C

ENST00000671824.1:c.1220T>C

ENST00000672743.1:n.169T>C

ENST00000673284.1:c.1157T>C

ENST00000336642.8:c.209T>C

ENST00000345378.6:c.1160T>C

ENST00000395796.7:c.1154T>C

ENST00000403799.7:c.1157T>C

ENST00000437084.1:c.1106T>C

ENST00000459642.1:n.537T>C

ENST00000616242.4:c.1154T>C

NM_000162.3:c.1157T>C

NM_033507.1:c.1160T>C

NM_033508.1:c.1154T>C

NM_000162.4:c.1157T>C

NM_001354800.1:c.1157T>C

NM_001354801.1:c.146T>C

NM_001354802.1:c.17T>C

NM_001354803.1:c.191T>C

NM_033507.2:c.1160T>C

NM_033508.2:c.1154T>C

NM_033507.3:c.1160T>C

NM_033508.3:c.1154T>C

NM_001354803.2:c.191T>C

Pathogenic

PP4_Moderate PS2 PP3 PP2 PM2_Supporting PM5

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.1157T>C variant in the glucokinase gene, GCK, causes an amino acid change of leucine to proline at codon 286 (p.(Leu386Pro)) 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 0.984, 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 as a de novo occurrence with confirmed parental relationships in 1 individual with a clinical picture highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6-7.6 and negative antibodies) (PP4_Moderate, PS2; internal lab contributors). Another missense variant, c.1156C>G, p.(Leu386Val) has been interpreted as pathogenic by the ClinGen MDEP, and p.(Leu386Pro) has a greater Grantham distance (PM5). In summary, c.1157T>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): PS2, PP4_Moderate, PM2_supporting, PP2, PP3, PM5.

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).

PS2

This variant was identified as a de novo occurrence with confirmed parental relationships in 1 individual with a clinical picture highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6-7.6 and negative antibodies) (PS2; internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.984, 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).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting). gnomAD v4.0.0: 1 copy in European (Non-Finnish)

PM5

Another missense variant, c.1156C>G, p.(Leu386Val) has been interpreted as pathogenic by the ClinGen MDEP, and p.(Leu386Pro) has an equal or greater Grantham distance (PM5).

Approved on: 2024-04-28

Published on: 2024-04-28

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