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]

Variant: NM_033508.3:c.528A>T

CA367401656

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: cf133cb4-f481-42e9-a5f8-9ad58c26f746

Approved on: 2024-11-16

Published on: 2024-12-02

HGVS expressions

NM_033508.3:c.528A>T

NC_000007.14:g.44150017T>A

CM000669.2:g.44150017T>A

NC_000007.13:g.44189616T>A

CM000669.1:g.44189616T>A

NC_000007.12:g.44156141T>A

NG_008847.1:g.44407A>T

NG_008847.2:g.53154A>T

ENST00000395796.8:c.*529A>T

ENST00000616242.5:c.531A>T

ENST00000682635.1:n.1017A>T

ENST00000345378.7:c.534A>T

ENST00000403799.8:c.531A>T

ENST00000671824.1:c.531A>T

ENST00000673284.1:c.531A>T

ENST00000345378.6:c.534A>T

ENST00000395796.7:c.528A>T

ENST00000403799.7:c.531A>T

ENST00000437084.1:c.480A>T

ENST00000616242.4:c.528A>T

NM_000162.3:c.531A>T

NM_033507.1:c.534A>T

NM_033508.1:c.528A>T

NM_000162.4:c.531A>T

NM_001354800.1:c.531A>T

NM_033507.2:c.534A>T

NM_033508.2:c.528A>T

NM_000162.5:c.531A>T

NM_033507.3:c.534A>T

Likely Pathogenic

PP4_Moderate PP1 PP3 PP2 PM2_Supporting

PS4

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.530A>G variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to aspartic acid at codon 177 (p.(Glu177Asp)) 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 absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.86, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 22941762, 30663027). One of these individuals did have a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT with minimal increment (<3 mmol/l)) (PP4_Moderate; PMID: 22941762). Furthermore, this variant segregated with diabetes with three informative meioses in a single family (PP1, PMID: 22941762). In summary, c.530A>G 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): PP1, PP2, PP3, PP4_Moderate, PM2_Supporting.

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT with minimal increment (<3 mmol/l)) (PP4_Moderate; PMID: 22941762).

PP1

This variant segregated with diabetes with three informative meioses in a single family (PP1, PMID: 22941762).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.86, 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

This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 22941762, 30663027).

Curation History

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