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]

Link to SEPIO compliant JSON-LD document

CA367402547

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: a844329d-1a89-4a5a-961a-e438e3558f68

Approved on: 2024-03-15

Published on: 2024-03-15

HGVS expressions

NM_033508.3:c.360+1G>A

NC_000007.14:g.44152270C>T

CM000669.2:g.44152270C>T

NC_000007.13:g.44191869C>T

CM000669.1:g.44191869C>T

NC_000007.12:g.44158394C>T

NG_008847.1:g.42154G>A

NG_008847.2:g.50901G>A

ENST00000395796.8:c.*361+1G>A

ENST00000616242.5:c.363+1G>A

ENST00000682635.1:n.849+1G>A

ENST00000345378.7:c.366+1G>A

ENST00000403799.8:c.363+1G>A

ENST00000671824.1:c.363+1G>A

ENST00000673284.1:c.363+1G>A

ENST00000345378.6:c.366+1G>A

ENST00000395796.7:c.360+1G>A

ENST00000403799.7:c.363+1G>A

ENST00000437084.1:c.363+1G>A

ENST00000616242.4:c.360+1G>A

NM_000162.3:c.363+1G>A

NM_033507.1:c.366+1G>A

NM_033508.1:c.360+1G>A

NM_000162.4:c.363+1G>A

NM_001354800.1:c.363+1G>A

NM_033507.2:c.366+1G>A

NM_033508.2:c.360+1G>A

NM_000162.5:c.363+1G>A

NM_033507.3:c.366+1G>A

Pathogenic

PVS1 PM2_Supporting PP1

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.363+1G>A variant in the glucokinase gene, GCK, is predicted to remove a canonical splice donor site in intron 3 of NM_000162.5. This variant is predicted to cause skipping of biologically relevant exon 3 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 segregated with hyperglycemia, with three informative meioses in one family (PP1; PMID:10447526). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID:10447526). In summary, c.363+1G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_Supporting, PP1.

PVS1

This variant is predicted to cause skipping of biologically-relevant exon 3 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).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting). gnomAD v4.0.0: One allele in European (non-Finnish)

PP1

This variant segregated with hyperglycemia, with three informative meioses in one family (PP1; PMID:10447526).

PP4

This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID:10447526).

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