Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003330332 | SCV004037465 | pathogenic | Monogenic diabetes | 2023-09-08 | reviewed by expert panel | curation | 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. |
| Ambry Genetics | RCV002380620 | SCV002695490 | pathogenic | Maturity onset diabetes mellitus in young | 2016-03-21 | criteria provided, single submitter | clinical testing | The c.1295_1297delCCAinsGCCG pathogenic mutation, located in coding exon 10 of the GCK gene, results from the deletion of 3 nucleotides and insertion of 4 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.P432Rfs*27). This mutation was first described in a proband with a clinical diagnosis of MODY. The mutation reportedly co-segregated with disease in three of her family members and in none of the normoglycemic relatives (Cappelli A, Diabetes Res. Clin. Pract. 2009 Mar; 83(3):e72-4). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). |