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_000162.5(GCK):c.118G>A (p.Glu40Lys)

Curation Version - 1.2
Curation History
JSON LD for Version 1.2

CA201503

195024 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: a6580baa-8994-4038-8172-c07d1652074a

Approved on: 2025-01-29

Published on: 2025-01-29

HGVS expressions

NM_000162.5:c.118G>A

NM_000162.5(GCK):c.118G>A (p.Glu40Lys)

NC_000007.14:g.44153391C>T

CM000669.2:g.44153391C>T

NC_000007.13:g.44192990C>T

CM000669.1:g.44192990C>T

NC_000007.12:g.44159515C>T

NG_008847.1:g.41033G>A

NG_008847.2:g.49780G>A

ENST00000395796.8:c.*116G>A

ENST00000616242.5:c.118G>A

ENST00000682635.1:n.604G>A

ENST00000345378.7:c.121G>A

ENST00000403799.8:c.118G>A

ENST00000671824.1:c.118G>A

ENST00000673284.1:c.118G>A

ENST00000345378.6:c.121G>A

ENST00000395796.7:c.115G>A

ENST00000403799.7:c.118G>A

ENST00000437084.1:c.118G>A

ENST00000476008.1:n.553G>A

ENST00000616242.4:c.115G>A

NM_000162.3:c.118G>A

NM_033507.1:c.121G>A

NM_033508.1:c.115G>A

NM_000162.4:c.118G>A

NM_001354800.1:c.118G>A

NM_033507.2:c.121G>A

NM_033508.2:c.115G>A

NM_033507.3:c.121G>A

NM_033508.3:c.115G>A

Pathogenic

PP1_Strong PM3_Supporting PM2_Supporting PS4 PS3_Moderate PP3 PP2 PP4_Moderate

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.118G>A variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to lysine at codon 40 (p.(Glu40Lys)) 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3). It is absent from gnomAD v2.1 and v4.1 (PM2_Supporting). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.069, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID: 25015100). This variant was identified in at least 33 unrelated individuals with hyperglycemia (PS4; PMID: 22332836, 29207974, 25015100, Internal lab contributors). This variant segregated with hyperglycemia, with four informative meioses in three families (PP1_Strong; PMID: 24804978, Internal lab contributors). 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%, antibody negative) (PP4_Moderate; Internal lab contributor). This variant has been detected in the homozygous state in one individual with neonatal diabetes (PM3_Supporting; PMID: 25015100). In summary, c.118G>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): PS4, PP4_Moderate, PS3_Moderate, PP1_Strong, PP2, PP3, PM2_Supporting, PM3_Supporting

PP1_Strong

This variant segregated with hyperglycemia, with four informative meioses in three families (PP1_Strong; PMID: 24804978, Internal lab contributors).

PM3_Supporting

This variant has been detected in the homozygous state in one individual with neonatal diabetes (PMID: 25015100)

PM2_Supporting

Absent in gnomAD v2.1 and v4.1 (PM2_Supporting).

PS4

This variant was identified in at least 33 unrelated individuals with hyperglycemia (PS4; PMID: 22332836, 29207974, 25015100, Internal lab contributors)

PS3_Moderate

MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.069, which is below the MDEP cutoff (<0.5) (PS3_Moderate, PMID: 25015100).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967, 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).

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%, antibody negative) (PP4_Moderate; Internal lab contributor).

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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