Variant: NM_001354803.2:c.402del

CA2017997779

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 8c1172cd-9ba7-4c5e-8711-2c33aa4ac895

Approved on: 2023-06-19

Published on: 2023-06-19

HGVS expressions

NM_001354803.2:c.402del
NC_000007.14:g.44145167del
CM000669.2:g.44145167del
NC_000007.13:g.44184766del
CM000669.1:g.44184766del
NC_000007.12:g.44151291del
NG_008847.1:g.49258del
NG_008847.2:g.58005del
ENST00000395796.8:c.*1366del
ENST00000616242.5:c.*488del
ENST00000683378.1:n.594del
ENST00000336642.9:c.402del
ENST00000345378.7:c.1371del
ENST00000403799.8:c.1368del
ENST00000671824.1:c.1431del
ENST00000672743.1:n.380del
ENST00000673284.1:c.1368del
ENST00000336642.8:n.420del
ENST00000345378.6:c.1371del
ENST00000395796.7:c.1365del
ENST00000403799.7:c.1368del
ENST00000437084.1:c.1317del
ENST00000459642.1:n.748del
ENST00000616242.4:n.1365del
NM_000162.3:c.1368del
NM_033507.1:c.1371del
NM_033508.1:c.1365del
NM_000162.4:c.1368del
NM_001354800.1:c.1368del
NM_001354801.1:c.357del
NM_001354802.1:c.228del
NM_001354803.1:c.402del
NM_033507.2:c.1371del
NM_033508.2:c.1365del
NM_000162.5:c.1368del
NM_033507.3:c.1371del
NM_033508.3:c.1365del

Likely Pathogenic

• Met criteria codes: PVS1 PM2_Supporting

• Not Met criteria codes: PS4 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 1.2.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1368del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 457 (NM_000545.6), adding 157 novel amino acids before encountering a stop codon (p.(Cys457Valfs157)). 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 2.1.1 (PM2_Supporting). In summary, c.1368del 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

• 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).
• PM2_Supporting: Absent in gnomAD

Not Met criteria codes

• PS4: One case by internal lab contributor, no clinical information provided
• PP4: No case-level information provided