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>C

CA367403045

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: 0e1ec57f-afe3-460d-b3a6-d839b66635d3

Approved on: 2024-12-02

Published on: 2024-12-02

HGVS expressions

NM_033508.3:c.229G>C

NC_000007.14:g.44152402C>G

CM000669.2:g.44152402C>G

NC_000007.13:g.44192001C>G

CM000669.1:g.44192001C>G

NC_000007.12:g.44158526C>G

NG_008847.1:g.42022G>C

NG_008847.2:g.50769G>C

ENST00000395796.8:c.*230G>C

ENST00000616242.5:c.232G>C

ENST00000682635.1:n.718G>C

ENST00000345378.7:c.235G>C

ENST00000403799.8:c.232G>C

ENST00000671824.1:c.232G>C

ENST00000673284.1:c.232G>C

ENST00000345378.6:c.235G>C

ENST00000395796.7:c.229G>C

ENST00000403799.7:c.232G>C

ENST00000437084.1:c.232G>C

ENST00000616242.4:c.229G>C

NM_000162.3:c.232G>C

NM_033507.1:c.235G>C

NM_033508.1:c.229G>C

NM_000162.4:c.232G>C

NM_001354800.1:c.232G>C

NM_033507.2:c.235G>C

NM_033508.2:c.229G>C

NM_000162.5:c.232G>C

NM_033507.3:c.235G>C

Pathogenic

PP3 PP2 PM1 PP4_Moderate PM2_Supporting PP1_Strong

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>C variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to histidine at codon 78 (p.(Asp78His)) 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). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.971, 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: 14517956, 28842611, 34440516). 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 a three generation family history) (PP4_Moderate; PMID: 34440516). Additonally, this variant segregated with hyperglycemia, with at least 5 informative meioses in a single family (PP1_Strong; PMID: 36257325, internal lab contributors). In summary, c.232G>C 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, PP1_Strong).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.971, 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).

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 (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and a three generation family history) (PP4_Moderate; PMID: 34440516).

PM2_Supporting

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

PP1_Strong

This variant segregated with hyperglycemia, with at least 5 informative meioses in a single family (PP1_Strong; PMID: 36257325, 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: 14517956, 28842611, 34440516).

Curation History

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