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_001354803.2:c.145T>C

CA367398947

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 0430392f-97ae-4337-9960-d87aeb030b65

HGVS expressions

NM_001354803.2:c.145T>C

NC_000007.14:g.44145639A>G

CM000669.2:g.44145639A>G

NC_000007.13:g.44185238A>G

CM000669.1:g.44185238A>G

NC_000007.12:g.44151763A>G

NG_008847.1:g.48785T>C

NG_008847.2:g.57532T>C

ENST00000395796.8:c.*1109T>C

ENST00000616242.5:c.*231T>C

ENST00000683378.1:n.337T>C

ENST00000336642.9:c.145T>C

ENST00000345378.7:c.1114T>C

ENST00000403799.8:c.1111T>C

ENST00000671824.1:c.1174T>C

ENST00000672743.1:n.123T>C

ENST00000673284.1:c.1111T>C

ENST00000336642.8:n.163T>C

ENST00000345378.6:c.1114T>C

ENST00000395796.7:c.1108T>C

ENST00000403799.7:c.1111T>C

ENST00000437084.1:c.1060T>C

ENST00000459642.1:n.491T>C

ENST00000616242.4:n.1108T>C

NM_000162.3:c.1111T>C

NM_033507.1:c.1114T>C

NM_033508.1:c.1108T>C

NM_000162.4:c.1111T>C

NM_001354800.1:c.1111T>C

NM_001354801.1:c.100T>C

NM_001354802.1:c.-30T>C

NM_001354803.1:c.145T>C

NM_033507.2:c.1114T>C

NM_033508.2:c.1108T>C

NM_000162.5:c.1111T>C

NM_033507.3:c.1114T>C

NM_033508.3:c.1108T>C

Likely Pathogenic

PP4_Moderate PM5_Supporting PM2_Supporting PP3 PP2

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 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1111T>C variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to arginine at codon 371 (p.(Cys371Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.98, 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 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) (internal lab contributors). Another missense variant, c.1112G>T p.(Cys371Phe), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.(Cys371Arg) (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PP4_Moderate, PM5_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 negative antibodies) (internal lab contributors).

PM5_Supporting

Another missense variant, c.1112G>T p.(Cys371Phe), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.(Cys371Arg)(PM5_Supporting).

PM2_Supporting

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

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.98, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PP2

GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2).

PP1

This variant segregated with diabetes/hyperglycemia with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors).

Approved on: 2023-08-09

Published on: 2023-08-10

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