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>A (p.Asp160Asn)

CA367401849

447404 (ClinVar)

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: 13354932-69db-4514-a2f6-05aca270081f

Approved on: 2026-01-22

Published on: 2026-01-28

HGVS expressions

NM_000162.5(GCK):c.478G>A (p.Asp160Asn)

NM_000162.5:c.478G>A

NC_000007.14:g.44150961C>T

CM000669.2:g.44150961C>T

NC_000007.13:g.44190560C>T

CM000669.1:g.44190560C>T

NC_000007.12:g.44157085C>T

NG_008847.1:g.43463G>A

NG_008847.2:g.52210G>A

ENST00000395796.8:c.*476G>A

ENST00000616242.5:c.478G>A

ENST00000682635.1:n.964G>A

ENST00000345378.7:c.481G>A

ENST00000403799.8:c.478G>A

ENST00000671824.1:c.478G>A

ENST00000673284.1:c.478G>A

ENST00000345378.6:c.481G>A

ENST00000395796.7:c.475G>A

ENST00000403799.7:c.478G>A

ENST00000437084.1:c.427G>A

ENST00000616242.4:c.475G>A

NM_000162.3:c.478G>A

NM_033507.1:c.481G>A

NM_033508.1:c.475G>A

NM_000162.4:c.478G>A

NM_001354800.1:c.478G>A

NM_033507.2:c.481G>A

NM_033508.2:c.475G>A

NM_033507.3:c.481G>A

NM_033508.3:c.475G>A

Pathogenic

PS3_Moderate PP1_Strong PP4_Moderate PP3 PP2 PS4 PM2_Supporting

PM5 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 3.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.478G>A variant in the glucokinase gene, GCK, causes an amino acid change of aspartate to asparagine at codon 160 (p.(Asp160Asn)) 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 has a Grpmax filtering allele frequency of 7.90e-7 in gnomAD v4.1.0, which is below the ClinGen MDEP threshold of 0.000003 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.712, which is greater than the MDEP VCEP threshold of 0.70 (PP3). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.29 (recalculated using updated RAI equation), which is below the MDEP cutoff (<0.5) (PMID: 25015100). This variant was identified in at least 33 unrelated individuals with hyperglycemia (PS4; PMID: 36257325, 25015100, internal lab contributors). Furthermore, at least one of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% detected incidentally in a pediatric patient and antibody negative ) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia, with at least 21 informative meioses in ten families with hyperglycemia (PP1_Strong; PMID: 25015100, 36257325, internal lab contributors). Other missense variants at the same amino acid position have been classified as pathogenic (c.478G>C (p.Asp160His)) and likely pathogenic (c.480T>A and c.480T>G (p.Asp160Glu)); however, PM5 was not applied to avoid circularity as p.Asp160Asn contributed to the classification of the other variants at this residue. In summary, c.478G>A 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): PS4, PP1_Strong, PS3_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting

PS3_Moderate

MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.29 (recalculated using updated RAI equation), which is below the MDEP cutoff (<0.5) (PMID: 25015100).

PP1_Strong

This variant segregated with hyperglycemia, with at least 21 informative meioses in ten families with hyperglycemia (PP1_Strong; PMID: 25015100, 36257325, internal lab contributors)

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% detected incidentally in a pediatric patient and antibody negative ) (PP4_Moderate; internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.712, 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).

PS4

This variant was identified in at least 33 unrelated individuals with hyperglycemia (PS4; PMID: 36257325, 25015100, internal lab contributors).

PM2_Supporting

This variant has a Grpmax filtering allele frequency of 7.90e-7 in gnomAD v4.1.0, which is below the ClinGen MDEP threshold of 0.000003 (PM2_Supporting).

PM5

Other missense variants at the same amino acid position have been classified as pathogenic (c.478G>C (p.Asp160His)) and likely pathogenic (c.480T>A and c.480T>G (p.Asp160Glu)); however, PM5 was not applied to avoid circularity as p.Asp160Asn contributed to the classification of the other variants at this residue.

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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