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

dbSNP: rs730882034

Total submissions: 5

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