ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.256C>T (p.Pro86Ser) (rs398123481)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
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.
Ambry Genetics RCV000492763 SCV000580953 pathogenic Hereditary cancer-predisposing syndrome 2018-09-29 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Well-characterized mutation at same position;Structural Evidence
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.
Invitae RCV001059327 SCV001223949 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-05-01 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 86 of the VHL protein (p.Pro86Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals and families affected with von Hippel-Lindau syndrome and to segregate with disease in families (PMID: 8634692, 9829912, 19464396, 27057652, 27527340). This variant is also known as 469C>T, Pro157Ser in the literature. ClinVar contains an entry for this variant (Variation ID: 178692). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant disrupts the p.Pro86 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 7728151,9829911, 11257211, 17024664, 19408298), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
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

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