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.1020-1G>C

CA213704

36170 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: e6b07542-2171-4ef9-8c9a-917e08344fb9

HGVS expressions

NM_000162.5:c.1020-1G>C

NM_000162.5(GCK):c.1020-1G>C

NC_000007.14:g.44145731C>G

CM000669.2:g.44145731C>G

NC_000007.13:g.44185330C>G

CM000669.1:g.44185330C>G

NC_000007.12:g.44151855C>G

NG_008847.1:g.48693G>C

NG_008847.2:g.57440G>C

ENST00000395796.8:c.*1018-1G>C

ENST00000616242.5:c.*140-1G>C

ENST00000683378.1:n.246-1G>C

ENST00000336642.9:c.54-1G>C

ENST00000345378.7:c.1023-1G>C

ENST00000403799.8:c.1020-1G>C

ENST00000671824.1:c.1083-1G>C

ENST00000672743.1:n.32-1G>C

ENST00000673284.1:c.1020-1G>C

ENST00000336642.8:c.72-1G>C

ENST00000345378.6:c.1023-1G>C

ENST00000395796.7:c.1017-1G>C

ENST00000403799.7:c.1020-1G>C

ENST00000437084.1:c.969-1G>C

ENST00000459642.1:n.399G>C

ENST00000473353.1:n.318-1G>C

ENST00000616242.4:c.1017-1G>C

NM_000162.3:c.1020-1G>C

NM_033507.1:c.1023-1G>C

NM_033508.1:c.1017-1G>C

NM_000162.4:c.1020-1G>C

NM_001354800.1:c.1020-1G>C

NM_001354801.1:c.9-1G>C

NM_001354802.1:c.-121-1G>C

NM_001354803.1:c.54-1G>C

NM_033507.2:c.1023-1G>C

NM_033508.2:c.1017-1G>C

NM_033507.3:c.1023-1G>C

NM_033508.3:c.1017-1G>C

NM_001354803.2:c.54-1G>C

Pathogenic

PS1_Supporting PVS1 PM2_Supporting

PS4

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.1020-1G>C variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 8 of NM_000162.5. This variant is predicted to cause skipping of biologically-relevant exon 9 of 10, resulting in deletion of >10% of a protein encoded by 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 one individual with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 18248649). The c.1020G>A variant at the same canonical nucleotide has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.1020G>C has a similar predicted impact by Splice AI (0.99 and 0.99 for Acceptor Loss) (PS1_Supporting). In summary, c.1020-1G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0; approved 8/11/2023): PVS1, PM2_Supporting, PS1_Supporting. 

PS1_Supporting

The c.1020G>A variant at the same canonical nucleotide has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.1020G>C has a similar predicted impact by Splice AI (0.99 and 0.99 for Acceptor Loss) (PS1_Supporting).

PVS1

This variant is predicted to cause skipping of biologically-relevant exon 9 of 10, resulting in deletion of >10% of a protein encoded by 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).

PS4

This variant was identified in one individual with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 18248649).

Approved on: 2024-03-31

Published on: 2024-03-31

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