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.1120G>A (p.Val374Met)

CA367398877

447380 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: e13e694d-f8cf-4a87-9449-28f3b3801e86

HGVS expressions

NM_000162.5:c.1120G>A

NM_000162.5(GCK):c.1120G>A (p.Val374Met)

NC_000007.14:g.44145630C>T

CM000669.2:g.44145630C>T

NC_000007.13:g.44185229C>T

CM000669.1:g.44185229C>T

NC_000007.12:g.44151754C>T

NG_008847.1:g.48794G>A

NG_008847.2:g.57541G>A

ENST00000395796.8:c.*1118G>A

ENST00000616242.5:c.*240G>A

ENST00000683378.1:n.346G>A

ENST00000336642.9:c.154G>A

ENST00000345378.7:c.1123G>A

ENST00000403799.8:c.1120G>A

ENST00000671824.1:c.1183G>A

ENST00000672743.1:n.132G>A

ENST00000673284.1:c.1120G>A

ENST00000336642.8:c.172G>A

ENST00000345378.6:c.1123G>A

ENST00000395796.7:c.1117G>A

ENST00000403799.7:c.1120G>A

ENST00000437084.1:c.1069G>A

ENST00000459642.1:n.500G>A

ENST00000616242.4:c.1117G>A

NM_000162.3:c.1120G>A

NM_033507.1:c.1123G>A

NM_033508.1:c.1117G>A

NM_000162.4:c.1120G>A

NM_001354800.1:c.1120G>A

NM_001354801.1:c.109G>A

NM_001354802.1:c.-21G>A

NM_001354803.1:c.154G>A

NM_033507.2:c.1123G>A

NM_033508.2:c.1117G>A

NM_033507.3:c.1123G>A

NM_033508.3:c.1117G>A

NM_001354803.2:c.154G>A

Likely Pathogenic

PP3 PP2 PM2_Supporting PS4_Moderate PP1_Moderate PP4_Moderate

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.1120G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 374 (p.(Val374Met)) 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 0.952, 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 5 unrelated individuals with non-autoimmune/insulin-deficient diabetes (PS4_Moderate; Zubkova et al. World Journal of Personalized Medicine. 2017;1(1):40-48, internal lab contributors). This variant segregated with diabetes, with 3 informative meioses in 2 families with MODY (PP1_Moderate; internal lab contributors). 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). 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 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PS4_Moderate, PP1_Moderate, PP4_Moderate.

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.952, 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).

PS4_Moderate

This variant was identified in 5 unrelated individuals with non-autoimmune/insulin-deficient diabetes (PS4_Moderate; Zubkova et al. World Journal of Personalized Medicine. 2017;1(1):40-48, internal lab contributors).

PP1_Moderate

This variant segregated with diabetes, with 3 informative meioses in 2 families with MODY (PP1_Moderate; internal lab contributors).

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).

Approved on: 2023-11-03

Published on: 2023-11-03

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