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.1079C>A (p.Ser360Ter)

CA367399113

1679547 (ClinVar)

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: f78a7f33-0ea6-4e33-8a48-de91dd23b81a

Approved on: 2026-01-22

Published on: 2026-01-28

HGVS expressions

NM_000162.5(GCK):c.1079C>A (p.Ser360Ter)

NM_000162.5:c.1079C>A

NC_000007.14:g.44145671G>T

CM000669.2:g.44145671G>T

NC_000007.13:g.44185270G>T

CM000669.1:g.44185270G>T

NC_000007.12:g.44151795G>T

NG_008847.1:g.48753C>A

NG_008847.2:g.57500C>A

ENST00000395796.8:c.*1077C>A

ENST00000616242.5:c.*199C>A

ENST00000683378.1:n.305C>A

ENST00000336642.9:c.113C>A

ENST00000345378.7:c.1082C>A

ENST00000403799.8:c.1079C>A

ENST00000671824.1:c.1142C>A

ENST00000672743.1:n.91C>A

ENST00000673284.1:c.1079C>A

ENST00000336642.8:c.131C>A

ENST00000345378.6:c.1082C>A

ENST00000395796.7:c.1076C>A

ENST00000403799.7:c.1079C>A

ENST00000437084.1:c.1028C>A

ENST00000459642.1:n.459C>A

ENST00000473353.1:n.377C>A

ENST00000616242.4:c.1076C>A

NM_000162.3:c.1079C>A

NM_033507.1:c.1082C>A

NM_033508.1:c.1076C>A

NM_000162.4:c.1079C>A

NM_001354800.1:c.1079C>A

NM_001354801.1:c.68C>A

NM_001354802.1:c.-62C>A

NM_001354803.1:c.113C>A

NM_033507.2:c.1082C>A

NM_033508.2:c.1076C>A

NM_033507.3:c.1082C>A

NM_033508.3:c.1076C>A

NM_001354803.2:c.113C>A

Pathogenic

PP4_Moderate PP1_Strong PS4 PM2_Supporting PVS1

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.1079C>A variant in the glucokinase gene, GCK, results in a premature termination at codon 360 (p.(Ser360Ter)) of NM_000162.5. This variant, located in biologically-relevant exon 9 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in 11 unrelated individuals with hyperglycemia (PS4; PMID: 31638168, 9049484, ClinVar, internal lab contributors). Additionally, at least 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% and antibody negative) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia, with 16 informative meioses in one family (PP1_Strong; PMID: 9049484/internal lab contributors). In summary, c.1079C>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): PVS1, PS4, PP1_Strong, PP4_moderate, PM2_supporting.

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 antibody negative) (PP4_Moderate; internal lab contributors).

PP1_Strong

This variant segregated with hyperglycemia, with 16 informative meioses in one family (PP1_Strong; PMID: 9049484/internal lab contributors).

PS4

This variant was identified in 12 unrelated individuals with hyperglycemia (PS4; PMID: 9049484, 31638168, ClinVar, internal lab contributors).

PM2_Supporting

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

PVS1

This variant, located in biologically-relevant exon 9 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256).

Curation History

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