Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Genomic Diagnostic Laboratory, |
RCV000767272 | SCV000897824 | pathogenic | Von Hippel-Lindau syndrome | 2018-08-01 | criteria provided, single submitter | clinical testing | |
| Laboratory for Molecular Medicine, |
RCV000767272 | SCV001365786 | likely pathogenic | Von Hippel-Lindau syndrome | 2019-03-26 | criteria provided, single submitter | clinical testing | The p.Gln145PhefsX12 variant in VHL has not been previously reported in individuals with von Hippel-Lindau (VHL) syndrome or in large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 145 and leads to a premature termination codon 12 amino acids downstream. This termination codon occurs within the terminal 50 bases of the second to last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Different frameshift variants at this position (p.Gln145TyrfsX27, p.Gln145HisfsX28) have been reported in individuals with VHL syndrome (Stolle 1998, Peng 2017). Additionally, frameshift and other loss of function variants downstream of the p.Gln145PhefsX12 variant, including a truncating variant (p.Tyr175X) that has been determined to be pathogenic, have been reported in individuals with VHL syndrome (HGMD database, Stenson 2017), suggesting that this region of the VHL protein may play an important role in disease. In summary, although additional studies are required to fully establish its clinical significance, the p.Gln145PhefsX12 variant is likely pathogenic for autosomal dominant VHL syndrome based on predicted impact to the protein and absence from large population studies. ACMG/AMP Criteria applied: PVS1_Strong; PM2. |