Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003313269 | SCV004012151 | likely pathogenic | Monogenic diabetes | 2023-06-20 | reviewed by expert panel | curation | The c.1351del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 451 (NM_000162.5), adding 163 novel amino acids before encountering a stop codon (p.(Leu451TrpfsTer163)). 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). This variant was identified in two unrelated individuals with diabetes/elevated HbA1c; however, this number does not meet the MDEP cutoff for PS4_Moderate (internal lab contributors) One of these individuals has a clinical history suggestive of GCK-MODY; however, PP4 was unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, the c.1351del variant 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. |
| Gene |
RCV002288201 | SCV002578819 | likely pathogenic | not provided | 2022-09-27 | criteria provided, single submitter | clinical testing | Frameshift variant predicted to result in protein elongation, as the last 15 amino acids are replaced with 162 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge |