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.478G>C (p.Asp160His)

CA367401848

1743101 (ClinVar)

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: 97fc6147-5f89-4b85-8005-11318771bd5e

Approved on: 2026-01-22

Published on: 2026-01-28

HGVS expressions

NM_000162.5(GCK):c.478G>C (p.Asp160His)

NM_000162.5:c.478G>C

NC_000007.14:g.44150961C>G

CM000669.2:g.44150961C>G

NC_000007.13:g.44190560C>G

CM000669.1:g.44190560C>G

NC_000007.12:g.44157085C>G

NG_008847.1:g.43463G>C

NG_008847.2:g.52210G>C

ENST00000395796.8:c.*476G>C

ENST00000616242.5:c.478G>C

ENST00000682635.1:n.964G>C

ENST00000345378.7:c.481G>C

ENST00000403799.8:c.478G>C

ENST00000671824.1:c.478G>C

ENST00000673284.1:c.478G>C

ENST00000345378.6:c.481G>C

ENST00000395796.7:c.475G>C

ENST00000403799.7:c.478G>C

ENST00000437084.1:c.427G>C

ENST00000616242.4:c.475G>C

NM_000162.3:c.478G>C

NM_033507.1:c.481G>C

NM_033508.1:c.475G>C

NM_000162.4:c.478G>C

NM_001354800.1:c.478G>C

NM_033507.2:c.481G>C

NM_033508.2:c.475G>C

NM_033507.3:c.481G>C

NM_033508.3:c.475G>C

Pathogenic

PM2_Supporting PS4_Moderate PP1_Strong PP4 PP3 PP2 PM3 PM5

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 3.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.478G>C variant in the glucokinase gene, GCK, causes an amino acid change of aspartate to histidine at codon 160 (p.(Asp160His)) 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 v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.946, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 29056535, 30608898, 36257325). 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%) (PP4; PMID: 30608898). This variant segregated with hyperglycemia, with 19 informative meioses in two families (PP1_Strong; PMID: 30608898, internal lab contributors). This variant has been detected in two individuals with neonatal diabetes in the homozygous state (internal lab contributors) (PM3). Another missense variant at the same residue, c.478G>A (p.Asp160Asn), has been interpreted as pathogenic by the ClinGen MDEP, and p.Asp160Glu has an equal or greater Grantham distance (PM5). In summary, c.478G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.1.0, approved 10/10/2025): PP1_Strong, PS4_Moderate, PM3, PM5, PP2, PP3, PP4, PM2_Supporting.

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

PS4_Moderate

This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 29056535, 30608898, 36257325).

PP1_Strong

This variant segregated with hyperglycemia, with 19 informative meioses in two families (PP1_Strong; PMID: 30608898, internal lab contributor).

PP4

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%) (PP4; PMID: 30608898).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.946, 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).

PM3

This variant has been detected in two individuals with neonatal diabetes in the homozygous state (internal lab contributors) (PM3).

PM5

Another missense variant at the same residue, c.478G>A (p.Asp160Asn), has been interpreted as pathogenic by the ClinGen MDEP, and p.Asp160His has a greater Grantham distance (PM5).

Curation History

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