Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000492552 | SCV000580958 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-07-03 | criteria provided, single submitter | clinical testing | The p.W88C variant (also known as c.264G>T), located in coding exon 1 of the VHL gene, results from a G to T substitution at nucleotide position 264. The tryptophan at codon 88 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in a cohort of over 25,000 individuals who underwent multigene panel testing (eMERGE Consortium. Am J Hum Genet, 2019 09;105:588-605). A similar alteration resulting in the same amino acid change (W88C) but with a different nucleotide change (referred to as 477G/C) has been reported in one individual diagnosed with CNS hemangioblastomas (Gläsker S et al. J. Neurol. Neurosurg. Psychiatr. 1999 Dec;67(6):758-62). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV000537014 | SCV000626890 | pathogenic | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2022-03-08 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp88 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7728151, 8956040, 10567493, 17024664). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects VHL function (PMID: 21715564). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function. ClinVar contains an entry for this variant (Variation ID: 223171). This missense change has been observed in individuals with clinical features of von Hippel-Lindau (VHL) syndrome (PMID: 10567493; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 88 of the VHL protein (p.Trp88Cys). |
| Laboratory for Molecular Medicine, |
RCV000208827 | SCV000967005 | likely pathogenic | Von Hippel-Lindau syndrome | 2018-03-27 | criteria provided, single submitter | clinical testing | The p.Trp88Cys variant in VHL has been reported in at least 5 individuals with v on Hippel-Landau syndrome (VHL; Glasker 1999, Clinvar Variation ID: 223171), and was absent from large population studies. In vitro functional studies provide s ome evidence that the p.Trp88Cys variant may impact protein function (Reschestei ner 2011). Computational prediction tools and conservation analysis suggest that the p.Trp88Cys variant may impact the protein. Additionally, other missense va riants at this position (p.Trp88Arg and p.Trp88Ser) have been reported in indivi duals with VHL (Glasker 2001, Rocha 2003, Chen 1995, Ong 2007, Jilg 2012, Stanoj evic 2007, Wong 2016), suggesting that a change at this amino acid position is n ot tolerated. In summary, although additional studies are required to fully esta blish its clinical significance, the p.Trp88Cys variant is likely pathogenic. AC MG/AMP criteria applied (Richards 2015): PM2; PM5; PP3; PS3_supporting; PS4_supp orting. |
| Genomic Diagnostic Laboratory, |
RCV000208827 | SCV000264688 | likely pathogenic | Von Hippel-Lindau syndrome | 2016-02-26 | no assertion criteria provided | clinical testing |