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

Variant: NM_000162.5(GCK):c.1019+2T>G

CA341584

21075 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: a7342b5a-334b-4415-af5d-b5a1cf09e947

HGVS expressions

NM_000162.5:c.1019+2T>G

NM_000162.5(GCK):c.1019+2T>G

NC_000007.14:g.44146461A>C

CM000669.2:g.44146461A>C

NC_000007.13:g.44186060A>C

CM000669.1:g.44186060A>C

NC_000007.12:g.44152585A>C

NG_008847.1:g.47963T>G

NG_008847.2:g.56710T>G

ENST00000395796.8:c.*1017+2T>G

ENST00000616242.5:c.*139+2T>G

ENST00000683378.1:n.245+2T>G

ENST00000345378.7:c.1022+2T>G

ENST00000403799.8:c.1019+2T>G

ENST00000671824.1:c.1082+2T>G

ENST00000673284.1:c.1019+2T>G

ENST00000345378.6:c.1022+2T>G

ENST00000395796.7:c.1016+2T>G

ENST00000403799.7:c.1019+2T>G

ENST00000437084.1:c.968+2T>G

ENST00000473353.1:n.317+2T>G

ENST00000616242.4:c.1016+2T>G

NM_000162.3:c.1019+2T>G

NM_033507.1:c.1022+2T>G

NM_033508.1:c.1016+2T>G

NM_000162.4:c.1019+2T>G

NM_001354800.1:c.1019+2T>G

NM_001354801.1:c.8+158T>G

NM_033507.2:c.1022+2T>G

NM_033508.2:c.1016+2T>G

NM_033507.3:c.1022+2T>G

NM_033508.3:c.1016+2T>G

Pathogenic

PM3 PVS1 PP1_Strong PM2_Supporting

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 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1019+2T>G variant in the glucokinase gene, GCK, is predicted to remove a canonical splice donor site in intron 8 of NM_000162.5. It is predicted to cause an in-frame deletion of biologically-relevant exon 8 of 10, removing an important region of the protein (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes with 8 informative meioses in a family with MODY (PP1_Strong; PMID 16026363). This variant was identified individuals with diabetes; however, there was insufficient clinical information to evaluate for PP4. This variant has been detected in at least 2 individuals with neonatal diabetes. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant, confirmed in trans by parental/family testing (PMID 16026363). 1 individual was homozygous for the variant (PMID 16026363) (PM3). In summary, the evidence supports the classification of c.1019+2T>G as a pathogenic variant for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PVS1, PM3, PP1_Strong.

PM3

This variant has been detected in at least 2 individuals with neonatal diabetes. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant, confirmed in trans by parental/family testing (PMID 16026363). 1 individual was homozygous for the variant (PMID 16026363) (PM3).

PVS1

It is predicted to cause an in-frame deletion of biologically-relevant exon 8 of 10, removing an important region of the protein (PVS1).

PP1_Strong

This variant segregated with diabetes with 8 informative meioses in a family with MODY (PP1_Strong; PMID 16026363).

PM2_Supporting

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

PP4

This variant was identified individuals with diabetes; however, there was insufficient clinical information to evaluate for PP4.

Approved on: 2024-02-23

Published on: 2024-02-23

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