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

CA367398660

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: c490d374-e64e-4306-b284-be7e91e050d8

HGVS expressions

NM_001354803.2:c.200T>A

NC_000007.14:g.44145584A>T

CM000669.2:g.44145584A>T

NC_000007.13:g.44185183A>T

CM000669.1:g.44185183A>T

NC_000007.12:g.44151708A>T

NG_008847.1:g.48840T>A

NG_008847.2:g.57587T>A

ENST00000395796.8:c.*1164T>A

ENST00000616242.5:c.*286T>A

ENST00000683378.1:n.392T>A

ENST00000336642.9:c.200T>A

ENST00000345378.7:c.1169T>A

ENST00000403799.8:c.1166T>A

ENST00000671824.1:c.1229T>A

ENST00000672743.1:n.178T>A

ENST00000673284.1:c.1166T>A

ENST00000336642.8:c.218T>A

ENST00000345378.6:c.1169T>A

ENST00000395796.7:c.1163T>A

ENST00000403799.7:c.1166T>A

ENST00000437084.1:c.1115T>A

ENST00000459642.1:n.546T>A

ENST00000616242.4:c.1163T>A

NM_000162.3:c.1166T>A

NM_033507.1:c.1169T>A

NM_033508.1:c.1163T>A

NM_000162.4:c.1166T>A

NM_001354800.1:c.1166T>A

NM_001354801.1:c.155T>A

NM_001354802.1:c.26T>A

NM_001354803.1:c.200T>A

NM_033507.2:c.1169T>A

NM_033508.2:c.1163T>A

NM_000162.5:c.1166T>A

NM_033507.3:c.1169T>A

NM_033508.3:c.1163T>A

Likely Pathogenic

PM2_Supporting PP4 PP3 PP2 PS3_Moderate

PS4 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 1.3.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1166T>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to aspartic acid at codon 389 (p.(Val389Asp)) 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 0.961, which is greater than the MDEP VCEP threshold of 0.70 (PP3). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be <0.1, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID: 2145522). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 unrelated individuals with hyperglycemia, however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 23771925, 32741144, internal lab contributors). This variant segregated with hyperglycemia with 1 informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). In summary, c.1166T>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PS3_Moderate, PP2, PP3, PP4, PM2_Supporting.

PM2_Supporting

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

PP4

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%) (PP4; internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.961, 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).

PS3_Moderate

MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be <0.1, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID: 2145522).

PS4

This variant was identified in 3 unrelated individuals with hyperglycemia, however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 23771925, 32741144, internal lab contributors).

PP1

This variant segregated with hyperglycemia with 1 informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors).

Approved on: 2024-06-22

Published on: 2024-06-22

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