ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.256C>T (p.Pro86Ser) (rs398123481)

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 RCV000492763 SCV000580953 pathogenic Hereditary cancer-predisposing syndrome 2016-09-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Well-characterized mutation at same position,Structural Evidence
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000155449 SCV000264684 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing
GeneDx RCV000413630 SCV000490877 pathogenic not provided 2018-01-29 criteria provided, single submitter clinical testing This pathogenic variant is denoted VHL c.256C>T at the cDNA level, p.Pro86Ser (P86S) at the protein level, and results in the change of a Proline to a Serine (CCC>TCC). This variant has been reported in several individuals and families with von Hippel-Lindau syndrome (Zbar 1996, Yoshida 2000, Elli 2006, Corcos 2008, Ciotti 2009, Nordstrom-O'Brien 2010, Wu 2012, Yuan 2016). VHL Pro86Ser was not observed in large population cohorts (Lek 2016). This variant is located in the beta domain, which interacts with the oxygen-dependent degradation (ODD) domain of the HIF-alpha subunits (Yuen 2009). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000155449 SCV000697490 pathogenic Von Hippel-Lindau syndrome 2016-01-29 criteria provided, single submitter clinical testing Variant summary: This c.256C>T variant affects a conserved nucleotide, resulting in amino acid change from Pro to Ser in HIFalfa domain of VHL protein. 5/5 in-silico tools predict this variant to be damaging. The variant is absent from the large, broad ExAC control population. In literature, this variant has been reported multiple independent patients with Von Hippel-Lindau disease or related cancers, and has been shown to segregate with disease in at least one family. Other missense changes at this codon are also reported in association VHL disease, namely p.P86R, p.P86L and p.P86A, suggesting that this codon is likely to be a mutational hot-spot. One clinical lab (via ClinVar) and one reputable database classify this variant as pathogenic/likley pathogenic. Taken together, this variant has been classified as a Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000155449 SCV000205140 likely pathogenic Von Hippel-Lindau syndrome 2013-02-19 criteria provided, single submitter clinical testing The Pro86Ser variant in VHL has been reported in 12 individuals with clinical fe atures of Von Hippel-Lindau syndrome, was absent from 276 control chromosomes, a nd segregated with disease in four affected family members across three families (Whaley 1994, Kondo 1995, Olschwang 1998, Dollfus 2002, Elii 2006, Ong 2007, Co rcos 2008, Ciotti 2009, Wu 2012). Computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for o r against an impact to the protein, however, proline (Pro) at position 86 is hig hly conserved across evolutionarily distant species, suggesting that a change to this position may not be tolerated. In addition, other variants at this positio n (Pro86Ala, Pro86Leu, Pro86Arg, and Pro86His) have been identified in patients with the clinical features of Von Hippel-Lindau syndrome (HGMD database, UMD dat abase). In summary, this variant is likely to be pathogenic, though additional s tudies are required to fully establish its clinical significance.

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.