Description
The c.1372_1373del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 458 (NM_000162.6), adding 75 novel amino acids before encountering a stop codon (p.(Lys458GlufsTer75)). 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). Additionally, this variant is absent in gnomAD v.2.1.1 (PM2_Supporting). This variant was identified in 2 unrelated individuals with a clinical picture consistent with non-autoimmune/insulin-deficient diabetes, however PS4 cannot be applied because this number is below the MDEP threshold (internal lab contributors). This variant was identified in a case consistent with GCK-hyperglycemia but there was insufficient clinical information to evaluate for PP4 (internal lab contributors). This variant segregated with disease with one informative meiosis in a family with MODY, however this does not meet the thresholds for PP1 set by Jarvik and Browning (PMID 27236918) (internal lab contributors). In summary, c.1372_1373del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_Supporting.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
