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]

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Variant: NM_033508.3:c.500C>A

CA367401747

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 3167542c-9524-4f73-887b-0fec213ecaa1

Approved on: 2023-12-08

Published on: 2023-12-08

HGVS expressions

NM_033508.3:c.500C>A

NC_000007.14:g.44150045G>T

CM000669.2:g.44150045G>T

NC_000007.13:g.44189644G>T

CM000669.1:g.44189644G>T

NC_000007.12:g.44156169G>T

NG_008847.1:g.44379C>A

NG_008847.2:g.53126C>A

ENST00000395796.8:c.*501C>A

ENST00000616242.5:c.503C>A

ENST00000682635.1:n.989C>A

ENST00000345378.7:c.506C>A

ENST00000403799.8:c.503C>A

ENST00000671824.1:c.503C>A

ENST00000673284.1:c.503C>A

ENST00000345378.6:c.506C>A

ENST00000395796.7:c.500C>A

ENST00000403799.7:c.503C>A

ENST00000437084.1:c.452C>A

ENST00000616242.4:c.500C>A

NM_000162.3:c.503C>A

NM_033507.1:c.506C>A

NM_033508.1:c.500C>A

NM_000162.4:c.503C>A

NM_001354800.1:c.503C>A

NM_033507.2:c.506C>A

NM_033508.2:c.500C>A

NM_000162.5:c.503C>A

NM_033507.3:c.506C>A

Pathogenic

PP3 PP2 PM5 PM1 PP1_Strong PM2_Supporting 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 1.2.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.503C>A variant in the glucokinase gene, GCK, causes an amino acid change of threonine to asparagine at codon 168 (p.(Thr168Asn)) of NM_000162.5. This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.879, which is greater than the MDEP VCEP threshold of 0.70 (PP3). 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). Another missense variant, c.502A>G p.Thr168Ala, has been interpreted as pathogenic by the ClinGen MDEP, and p.Thr168Asn has a greater Grantham distance (PM5). 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). This variant segregated with diabetes/hyperglycemia, with 6 informative meioses in one family with MODY (PP1_Strong; internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.503C>A 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): PM1, PP3, PP2, PM5, PP4_Moderate, PP1_Strong, PM2_Supporting.

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.879, 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).

PM5

Another missense variant, c.502A>G p.Thr168Ala, has been interpreted as pathogenic by the ClinGen MDEP, and p.Thr168Asn has a greater Grantham distance (PM5).

PM1

This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1).

PP1_Strong

This variant segregated with diabetes/hyperglycemia, with 6 informative meioses in one family with MODY (PP1_Strong; internal lab contributors).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_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) (PP4_Moderate; internal lab contributors).

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