Variant: NM_001354803.2:c.425del

CA2573102976

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 97f80ba0-8d66-4523-8a8c-7d7e1d266044

Approved on: 2023-06-18

Published on: 2023-06-18

HGVS expressions

NM_001354803.2:c.425del
NC_000007.14:g.44145145del
CM000669.2:g.44145145del
NC_000007.13:g.44184744del
CM000669.1:g.44184744del
NC_000007.12:g.44151269del
NG_008847.1:g.49281del
NG_008847.2:g.58028del
ENST00000395796.8:c.*1389del
ENST00000616242.5:c.*511del
ENST00000683378.1:n.617del
ENST00000336642.9:c.425del
ENST00000345378.7:c.1394del
ENST00000403799.8:c.1391del
ENST00000671824.1:c.1454del
ENST00000672743.1:n.381+22del
ENST00000673284.1:c.1369+22del
ENST00000336642.8:n.443del
ENST00000345378.6:c.1394del
ENST00000395796.7:c.1388del
ENST00000403799.7:c.1391del
ENST00000437084.1:c.1340del
ENST00000459642.1:n.771del
ENST00000616242.4:n.1388del
NM_000162.3:c.1391del
NM_033507.1:c.1394del
NM_033508.1:c.1388del
NM_000162.4:c.1391del
NM_001354800.1:c.1369+22del
NM_001354801.1:c.380del
NM_001354802.1:c.229+22del
NM_001354803.1:c.425del
NM_033507.2:c.1394del
NM_033508.2:c.1388del
NM_000162.5:c.1391del
NM_033507.3:c.1394del
NM_033508.3:c.1388del

Likely Pathogenic

• Met criteria codes: PM2_Supporting PVS1

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 1.2.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1391del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 464 (NM_000162.5), adding 150 novel amino acids before encountering a stop codon (p.(Gly464AlafsTer150)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function 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). In summary, c.1391del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting

Met criteria codes

• PM2_Supporting: Absent in gnomAD v2.1.1 (PM2_Supporting).
• PVS1: This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256).