Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000132356 | SCV000187445 | pathogenic | Hereditary cancer-predisposing syndrome | 2019-04-17 | criteria provided, single submitter | clinical testing | The p.R64P pathogenic mutation (also known as c.191G>C), located in coding exon 1 of the VHL gene, results from a G to C substitution at nucleotide position 191. The arginine at codon 64 is replaced by proline, an amino acid with dissimilar properties. This mutation has been reported in multiple individuals and/or families diagnosed with VHL (van der Harst E et al. Int J Cancer. 1998 Jul 29;77(3):337-40; Hoffman MA et al. Hum. Mol. Genet. 2001 May;10:1019-27; Hes FJ et al. Clin Genet. 2007 Aug;72(2):122-9; Boedeker CC et al. J. Clin. Endocrinol. Metab. 2009 Jun;94:1938-44; Wittström E et al. Ophthalmic Genet. 2014 Jun;35:91-106). In addition, a 23-year-old female diagnosed with a neck PGL who had a family history of PCCs and clear cell renal cell carcinoma was found to carry this alteration, and her tumor showed LOH for the wild-type allele (Gaal J et al. J Clin Endocrinol Metab. 2009 Nov;94(11):4367-71). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Genomic Diagnostic Laboratory, |
RCV000208872 | SCV000264666 | pathogenic | Von Hippel-Lindau syndrome | 2018-08-01 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000475973 | SCV000553379 | pathogenic | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2024-01-05 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 64 of the VHL protein (p.Arg64Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Von Hippel-Lindau (VHL) syndrome and pheochromocytoma (PMID: 9663592, 17102083, 17661816, 19336503, 24555745). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2226). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects VHL function (PMID: 11331612, 15611064, 16452184). For these reasons, this variant has been classified as Pathogenic. |
| Prevention |
RCV000679019 | SCV000805324 | likely pathogenic | not provided | 2018-02-13 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000679019 | SCV004034858 | pathogenic | not provided | 2023-08-24 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); Also known as c.404G>A, p.(R105P); This variant is associated with the following publications: (PMID: 19408298, 18836774, 29748190, 21463266, 19336503, 9663592, 19808854, 17661816, 19576851, 17639058, 17102083, 20151405, 18043261, 26269449, 30877234, 28944243, 28646318, 11331612, 16452184, 15611064, 17700531, 12944410, 26846855, 32832168, 32487141, 24555745) |
| OMIM | RCV000002314 | SCV000022472 | pathogenic | Pheochromocytoma | 1998-07-29 | no assertion criteria provided | literature only |