ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.257C>T (p.Pro86Leu)

dbSNP: rs730882034
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492524 SCV000580955 pathogenic Hereditary cancer-predisposing syndrome 2021-10-07 criteria provided, single submitter clinical testing The p.P86L pathogenic mutation (also known as c.257C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide position 257. The proline at codon 86 is replaced by leucine, an amino acid with very few similar properties. This pathogenic mutation has been found in multiple individuals meeting clinical criteria for Von Hippel-Lindau syndrome with symptoms including retinal angiomas, CNS hemangioblastomas, renal cell carcinoma, and pancreatic cysts/tumors (Chen F et al. Hum. Mutat. 1995; 5(1):66-75; Kondo et al. Hum. Mol. Genet. 1995 Dec;4(12):2233-7; Yoshida M et al. Jpn. J. Cancer Res. 2000 Feb; 91(2):204-12; Ong KR et al. Hum. Mutat. 2007 Feb;28(2):143-9; Zhang J et al J. Cancer Res. Clin. Oncol. 2008 Nov;134(11):1211-8; Wong M et al. Chin J Cancer. 2016 Aug;35:79). Three unique alterations located at the same position, p.P86A, p.P86S, and p.P86R, have each been documented in the literature as having an association with Von Hippel-Lindau syndrome suggesting this codon may represent a mutation hotspot. Of note, the p.P86L (c.257C>T) alteration has also been reported as p.P157L (c.470C>T) in some literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000208836 SCV000697492 pathogenic Von Hippel-Lindau syndrome 2016-02-02 criteria provided, single submitter clinical testing Variant summary: c.257C>T affects a conserved nucleotide, resulting in amino acid change from Pro to Leu. 4/4 in-silico tools predict this variant to be damaging. This variant was not found in 102226 control chromosomes. This variant has been reported in multiple VHL pts with clear co-segregation of the variant with disease in the families. Variants P86A, P86R, and P86S are all listed as disease mutation in HGMD and have been reported in multiple publications, suggesting the codon 86 is a hypermutable amino acid and a hotspot for mutations. In addition, one clinical laboratory (via Clinvar) classified this variant as pathogenic. Taken together, this variant was classified as a Pathogenic.
Invitae RCV001382230 SCV001580902 pathogenic Chuvash polycythemia; Von Hippel-Lindau syndrome 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 86 of the VHL protein (p.Pro86Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with von Hippel-Lindau (VHL) syndrome (PMID: 7728151, 27527340; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.470C>T, p.Pro157Leu. ClinVar contains an entry for this variant (Variation ID: 182977). 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%. This variant disrupts the p.Pro86 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8634692, 9829912, 19464396, 27057652, 27527340). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000208836 SCV000264685 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing
Clinical Genomics Labs, University Health Network RCV000208836 SCV001950152 likely pathogenic Von Hippel-Lindau syndrome 2020-08-24 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.