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]

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Variant: NM_000162.5(GCK):c.680-2A>G

CA367400799

585924 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: c6062709-0cc0-4bb8-8a50-f982eb5fc052

Approved on: 2024-02-28

Published on: 2024-02-28

HGVS expressions

NM_000162.5:c.680-2A>G

NM_000162.5(GCK):c.680-2A>G

NC_000007.14:g.44147835T>C

CM000669.2:g.44147835T>C

NC_000007.13:g.44187434T>C

CM000669.1:g.44187434T>C

NC_000007.12:g.44153959T>C

NG_008847.1:g.46589A>G

NG_008847.2:g.55336A>G

ENST00000395796.8:c.*678-2A>G

ENST00000616242.5:c.680-2A>G

ENST00000345378.7:c.683-2A>G

ENST00000403799.8:c.680-2A>G

ENST00000671824.1:c.680-2A>G

ENST00000673284.1:c.680-2A>G

ENST00000345378.6:c.683-2A>G

ENST00000395796.7:c.677-2A>G

ENST00000403799.7:c.680-2A>G

ENST00000437084.1:c.629-2A>G

ENST00000616242.4:c.677-2A>G

NM_000162.3:c.680-2A>G

NM_033507.1:c.683-2A>G

NM_033508.1:c.677-2A>G

NM_000162.4:c.680-2A>G

NM_001354800.1:c.680-2A>G

NM_033507.2:c.683-2A>G

NM_033508.2:c.677-2A>G

NM_033507.3:c.683-2A>G

NM_033508.3:c.677-2A>G

Pathogenic

PM2_Supporting PS4 PVS1

PP4

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.680-2A>G variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 6 of NM_000162.5. This variant is predicted to cause skipping of biologically-relevant exon 7 of 10, resulting in a frameshift, leading 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 v2.1.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4: PMIDs: 19790256, 31704690, 36257325, 34362814, ClinVar ID:585924). At least 2 of these individuals had a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 31704690). In summary, c.680-2A>G 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, approved 8/11/2023): PVS1, PS4, PM2_Supporting.

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

PS4

This variant was identified in 7 unrelated individuals with hyperglycemia (PS4: PMIDs: 19790256, 31704690, 36257325, 34362814, ClinVar ID:585924).

PVS1

This variant is predicted to cause skipping of biologically-relevant exon 7 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256).

PP4

This variant was identified in at least 2 individuals with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 31704690).

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