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.56T>A (p.Ile19Asn)

CA367403826

2136531 (ClinVar)

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: 588c71a8-9a58-4904-8a95-4da3714631e8

Approved on: 2026-02-24

Published on: 2026-02-26

HGVS expressions

NM_000162.5:c.56T>A

NM_000162.5(GCK):c.56T>A (p.Ile19Asn)

NC_000007.14:g.44153453A>T

CM000669.2:g.44153453A>T

NC_000007.13:g.44193052A>T

CM000669.1:g.44193052A>T

NC_000007.12:g.44159577A>T

NG_008847.1:g.40971T>A

NG_008847.2:g.49718T>A

ENST00000395796.8:c.*54T>A

ENST00000616242.5:c.56T>A

ENST00000682635.1:n.542T>A

ENST00000345378.7:c.59T>A

ENST00000403799.8:c.56T>A

ENST00000671824.1:c.56T>A

ENST00000673284.1:c.56T>A

ENST00000345378.6:c.59T>A

ENST00000395796.7:c.53T>A

ENST00000403799.7:c.56T>A

ENST00000437084.1:c.56T>A

ENST00000476008.1:n.491T>A

ENST00000616242.4:c.53T>A

NM_000162.3:c.56T>A

NM_033507.1:c.59T>A

NM_033508.1:c.53T>A

NM_000162.4:c.56T>A

NM_001354800.1:c.56T>A

NM_033507.2:c.59T>A

NM_033508.2:c.53T>A

NM_033507.3:c.59T>A

NM_033508.3:c.53T>A

Pathogenic

PS4 PP1 PP3 PP2 PM3 PP4_Moderate PM2_Supporting

PS3 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.56T>A variant in the glucokinase gene, GCK, causes an amino acid change of isoleucine to asparagine at codon 19 (p.(Ile19Asn)) 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 an incomputable gnomAD v4.1.0 Grpmax filtering allele frequency due to no more than one copy in any subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (Grpmax FAF <= 0.000003) (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.861, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMID: 25665835, 33852230, 17573900, internal lab contributors). 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 negative antibody) (PP4_Moderate; internal lab contributors), and segregated with hyperglycemia, with two informative meioses in two families (PP1; PMID: 25665835, internal lab contributors). This variant has been detected in two siblings with neonatal diabetes who were compound heterozygous (confirmed in trans) for this variant and c.1322C>G p.Ser441Trp, which was classified as pathogenic by the MDEP VCEP (PMID: 25665835) (PM3). The relative activity index (RAI) of this variant was above the MDEP cutoff of 0.5 and a relative stability index was not calculated, so PS3 will not be applied (PMID: 25665835). In summary, c.56T>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, PP4_moderate, PP1, PM3, PP2, PP3, PM2_Supporting.

PS4

This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMID: 25665835, 33852230, 17573900, internal lab contributors).

PP1

This variant segregated with hyperglycemia, with two informative meioses in two families (PP1; PMID: 25665835, internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.861, 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 siblings with neonatal diabetes who were compound heterozygous (confirmed in trans) for this variant and c.1322C>G p.Ser441Trp, which was classified as pathogenic by the MDEP VCEP (PMID: 25665835) (PM3).

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 negative antibody) (PP4_Moderate; internal lab contributors).

PM2_Supporting

This variant has an incomputable gnomAD v4.1.0 Grpmax filtering allele frequency due to no more than one copy in any subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (Grpmax FAF <= 0.000003) (PM2_Supporting).

PS3

The relative activity index (RAI) of this variant was above the MDEP cutoff of 0.5 and a relative stability index was not calculated (PMID: 25665835).

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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