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.229G>A

CA367403047

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: d4ccd1e7-1a69-4c30-8a29-443c2cc6e5ce

Approved on: 2024-12-02

Published on: 2024-12-02

HGVS expressions

NM_033508.3:c.229G>A

NC_000007.14:g.44152402C>T

CM000669.2:g.44152402C>T

NC_000007.13:g.44192001C>T

CM000669.1:g.44192001C>T

NC_000007.12:g.44158526C>T

NG_008847.1:g.42022G>A

NG_008847.2:g.50769G>A

ENST00000395796.8:c.*230G>A

ENST00000616242.5:c.232G>A

ENST00000682635.1:n.718G>A

ENST00000345378.7:c.235G>A

ENST00000403799.8:c.232G>A

ENST00000671824.1:c.232G>A

ENST00000673284.1:c.232G>A

ENST00000345378.6:c.235G>A

ENST00000395796.7:c.229G>A

ENST00000403799.7:c.232G>A

ENST00000437084.1:c.232G>A

ENST00000616242.4:c.229G>A

NM_000162.3:c.232G>A

NM_033507.1:c.235G>A

NM_033508.1:c.229G>A

NM_000162.4:c.232G>A

NM_001354800.1:c.232G>A

NM_033507.2:c.235G>A

NM_033508.2:c.229G>A

NM_000162.5:c.232G>A

NM_033507.3:c.235G>A

Pathogenic

PM2_Supporting PP3 PP2 PM5_Strong PM1 PP4_Moderate

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.232G>A variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to asparagine at codon 78 (p.(Asp78Asn)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 and v4.1 (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 predicted to be deleterious by computational evidence, with a REVEL score of 0.947, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Furthermore, this variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 36257325, internal lab contributors). One of the individuals harboring this variant had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antiboides) (PP4_Moderate; internal lab contributors). Two other missense variants, c.234C>G (p.Asp78Glu) and c.232G>C (p.Asp78His) have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.232G>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): PM2_Supporting, PP2, PP3, PM1, PP4_Moderate, PM5_Strong.

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Absent from gnomAD v4.1

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.947, 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_Strong

Two other missense variants, c.234C>G (p.Asp78Glu) and c.232G>C (p.Asp78His) have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong).

PM1

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

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 3 generation family history of hyperglycemia) (PP4_Moderate; internal lab contributors).

PS4

This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 36257325, internal lab contributors).

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.