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

CA367398695

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 240528ae-8dc8-4e48-8ade-9c621fcd822d

HGVS expressions

NM_001354803.2:c.193G>A

NC_000007.14:g.44145591C>T

CM000669.2:g.44145591C>T

NC_000007.13:g.44185190C>T

CM000669.1:g.44185190C>T

NC_000007.12:g.44151715C>T

NG_008847.1:g.48833G>A

NG_008847.2:g.57580G>A

ENST00000395796.8:c.*1157G>A

ENST00000616242.5:c.*279G>A

ENST00000683378.1:n.385G>A

ENST00000336642.9:c.193G>A

ENST00000345378.7:c.1162G>A

ENST00000403799.8:c.1159G>A

ENST00000671824.1:c.1222G>A

ENST00000672743.1:n.171G>A

ENST00000673284.1:c.1159G>A

ENST00000336642.8:c.211G>A

ENST00000345378.6:c.1162G>A

ENST00000395796.7:c.1156G>A

ENST00000403799.7:c.1159G>A

ENST00000437084.1:c.1108G>A

ENST00000459642.1:n.539G>A

ENST00000616242.4:c.1156G>A

NM_000162.3:c.1159G>A

NM_033507.1:c.1162G>A

NM_033508.1:c.1156G>A

NM_000162.4:c.1159G>A

NM_001354800.1:c.1159G>A

NM_001354801.1:c.148G>A

NM_001354802.1:c.19G>A

NM_001354803.1:c.193G>A

NM_033507.2:c.1162G>A

NM_033508.2:c.1156G>A

NM_000162.5:c.1159G>A

NM_033507.3:c.1162G>A

NM_033508.3:c.1156G>A

Pathogenic

PP3 PP2 PM2_Supporting PP4_Moderate PS4_Moderate PP1_Strong

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.1159G>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to threonine at codon 387 (p.(Ala387Thr)) of NM_000162.5. This variant 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 is located in the larger hexokinase domain of the GCK gene (PMID: 31638168) but this variant does not reside in an amino acid that directly binds glucose or ATP, which is defined as critical for the protein’s function by the ClinGen MDEP, so it does not meet PM1. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.908, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant segregated with hyperglycemia, with at least 4 meioses in four families (PP1_Strong; PMID: 36257325). One of these probands (described PMID: 14517956) has a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and 2-hour increment on OGTT < 3mmol/L) (PP4_Moderate). In summary, c.1159G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (VCEP specifications version v1.3.0; approved 8/11/2023): PP1_Strong, PS4_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting

PP3

REVEL 0.908

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

Absent in gnomAD v2.1.

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 increment on OGTT < 3mmol/L) (PP4_Moderate; PMID: 14517956).

PS4_Moderate

This variant was identified in four unrelated individuals with hyperglycemia (PS4_Moderate; PMID:36257325).

PP1_Strong

This variant segregated with hyperglycemia, with at least 4 meioses in four families (PP1_Strong; PMID: 36257325).

PM1

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

Approved on: 2024-02-28

Published on: 2024-02-28

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