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.818A>C

CA367400483

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: 494ee228-ea9f-48a9-a7e2-94a3161a3984

Approved on: 2024-11-04

Published on: 2024-11-05

HGVS expressions

NM_033508.3:c.818A>C

NC_000007.14:g.44147692T>G

CM000669.2:g.44147692T>G

NC_000007.13:g.44187291T>G

CM000669.1:g.44187291T>G

NC_000007.12:g.44153816T>G

NG_008847.1:g.46732A>C

NG_008847.2:g.55479A>C

ENST00000395796.8:c.*819A>C

ENST00000616242.5:c.821A>C

ENST00000345378.7:c.824A>C

ENST00000403799.8:c.821A>C

ENST00000671824.1:c.821A>C

ENST00000673284.1:c.821A>C

ENST00000345378.6:c.824A>C

ENST00000395796.7:c.818A>C

ENST00000403799.7:c.821A>C

ENST00000437084.1:c.770A>C

ENST00000616242.4:c.818A>C

NM_000162.3:c.821A>C

NM_033507.1:c.824A>C

NM_033508.1:c.818A>C

NM_000162.4:c.821A>C

NM_001354800.1:c.821A>C

NM_033507.2:c.824A>C

NM_033508.2:c.818A>C

NM_000162.5:c.821A>C

NM_033507.3:c.824A>C

Pathogenic

PP1_Strong PP4_Moderate PS4_Moderate PP3 PP2 PM2_Supporting

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.821A>C variant in the glucokinase gene, GCK, is a missense variant resulting in an amino acid change of aspartic acid to alanine at codon 274 (p.(Asp274Ala)) 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). Additionally, it is predicted to be deleterious by computational evidence, with a REVEL score of 0.988, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in five individuals with hyperglycemia (PS4_Moderate, internal lab contributors). Additionally, one of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributor). This variant segregated with hyperglycemia, with 4 informative meioses in two families (PP1_Strong; internal lab contributors). In summary, c.821A>C variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PS4_Moderate, PM2_Supporting, PP1_Strong, PP2, PP3, PP4_Moderate.

PP1_Strong

This variant segregated with hyperglycemia, with 4 informative meioses in two families (PP1_Strong; 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% [2 occurrences each] and negative antibodies)(PP4_Moderate; internal lab contributor).

PS4_Moderate

This variant was identified in five individuals with hyperglycemia (PS4_Moderate, internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.988, 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).

PM1

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

Curation History

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