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

CA367402547

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

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

• Met criteria codes: PP1 PVS1 PM2_Supporting

• Not Met criteria codes: PP4

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

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.

Met criteria codes

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

Not Met criteria codes

• 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).