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_033508.3:c.1016+1G>T

CA367399678

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: f35e0db8-5d0b-4d73-bb25-f51e4061b3a5

Approved on: 2023-11-24

Published on: 2023-11-24

HGVS expressions

NM_033508.3:c.1016+1G>T

NC_000007.14:g.44146462C>A

CM000669.2:g.44146462C>A

NC_000007.13:g.44186061C>A

CM000669.1:g.44186061C>A

NC_000007.12:g.44152586C>A

NG_008847.1:g.47962G>T

NG_008847.2:g.56709G>T

ENST00000395796.8:c.*1017+1G>T

ENST00000616242.5:c.*139+1G>T

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

ENST00000345378.7:c.1022+1G>T

ENST00000403799.8:c.1019+1G>T

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

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

ENST00000345378.6:c.1022+1G>T

ENST00000395796.7:c.1016+1G>T

ENST00000403799.7:c.1019+1G>T

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

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

ENST00000616242.4:c.1016+1G>T

NM_000162.3:c.1019+1G>T

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

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

NM_000162.4:c.1019+1G>T

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

NM_001354801.1:c.8+157G>T

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

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

NM_000162.5:c.1019+1G>T

NM_033507.3:c.1022+1G>T

Pathogenic

PS1_Supporting PM2_Supporting PVS1

PP4 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.1019+1G>T variant in the glucokinase gene, GCK, is predicted to remove a canonical splice donor site in intron 8 of NM_000162.5. This variant is predicted to cause skipping of biologically-relevant exon 9 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). It was identified in an individual with hyperglycemia; however, PP4 is not met because they do not meet MDEP requirements for PP4 (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PMID: 34440516). The c.1019+1G>A variant at the same canonical nucleotide has a similar predicted donor loss score by Splice AI (.96 and .96), and has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP (PS1_Supporting). In summary, c.1019+1G>T 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, PS1_Supporting, PM2_Supporting,

PS1_Supporting

The c.1019+1G>A variant at the same canonical nucleotide has a similar donor loss score by Splice AI (0.96 and 0.96), and has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP (PS1_Supporting).

PM2_Supporting

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

PVS1

This variant is predicted to cause skipping of biologically-relevant exon 9 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 an individual with hyperglycemia; however, PP4 is not met because they do not meet MDEP requirements for PP4 (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PMID: 15928245).

PS4

One case

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