Description
The c.1295_1297delinsCGGC variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 432 (NM_000162.5), adding 27 novel amino acids before encountering a stop codon (p.(Pro432ArgfsTer27)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history suggestive of GCK-hyperglycemia, but PP4 could not be evaluated due to insufficient clinical information (PMID 19150152). This variant segregated with diabetes with 3 informative meiosis in this individual's family (PP1; PMID 19150152). In summary, the c.1295_1297delinsGCCG variant 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, PP1, 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 |
