Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000756901 | SCV000884874 | pathogenic | not provided | 2017-11-03 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001855883 | SCV002234898 | pathogenic | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2022-07-14 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg161 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12000816, 14767570, 20120764, 23842656, 25371412). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 618484). This missense change has been observed in individuals with clinical features of von Hippel-Lindau syndrome (PMID: 8707293, 10567493, 19464396, 23512077). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 161 of the VHL protein (p.Arg161Gly). |
| Ambry Genetics | RCV002332535 | SCV002634004 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-08-03 | criteria provided, single submitter | clinical testing | The p.R161G pathogenic mutation (also known as c.481C>G), located in coding exon 3 of the VHL gene, results from a C to G substitution at nucleotide position 481. The arginine at codon 161 is replaced by glycine, an amino acid with dissimilar properties. This mutation has been identified in multiple individuals and families with histories consistent with Von Hippel-Lindau syndrome (Glavac D et al. Hum. Genet., 1996 Sep;98:271-80; Gläsker S et al. J. Neurol. Neurosurg. Psychiatry, 1999 Dec;67:758-62; Murgia A et al. Hum. Mutat., 2000 Jan;15:114; Ciotti P et al. Eur J Med Genet 2009 May;52:311-4; Kim HJ et al. Laryngoscope, 2013 Feb;123:477-83; Fishbein L et al. Ann. Surg. Oncol., 2013 May;20:1444-50; Krauss T et al. Endocr. Relat. Cancer, 2018 09;25:783-793). One study predicted this alteration to be pathogenic using a Bayesian model that incorporates phylogenetic, biochemical, and structural features (Cai Z et al. Hum. Mutat., 2004 Aug;24:178-84). In another study, in vitro experiments suggest that mutations affecting residue 161, such as p.R161G, negatively impact elongin-binding activity (Ohh M et al. J. Clin. Invest., 1999 Dec;104:1583-91). Of note, this alteration is also designated as 694C>G in the published literature. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |