Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular 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. |
| Gene |
RCV000413630 | SCV000490877 | pathogenic | not provided | 2022-11-03 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.469C>T, p.P157S, p.P127S; This variant is associated with the following publications: (PMID: 25562111, 7977367, 23660872, 18836774, 8956040, 9829912, 15300849, 8634692, 16952288, 27057652, 22357542, 20151405, 17024664, 10761708, 16506495, 19464396, 19215943, 18580449, 27527340, 33774214, 34926252, Al-Hadlaq[article]2022) |
| Ambry Genetics | RCV000492763 | SCV000580953 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-04-06 | criteria provided, single submitter | clinical testing | The p.P86S pathogenic mutation (also known as c.256C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide position 256. The proline at codon 86 is replaced by serine, an amino acid with similar properties. This mutation has been detected in multiple individuals meeting clinical criteria for Von Hippel-Lindau (VHL) disease with symptoms including retinal angiomas, cerebellar hemangioblastomas, pheochromocytomas, renal cell carcinoma, and pancreatic cysts and tumors (Kondo K et. al. Hum. Mol. Genet. 1995 Dec;4:2233-7; Ong KR, et al. Hum. Mutat. 2007 Feb;28:143-9; Whaley JM et al. Am. J. Hum. Genet. 1994 Dec;55:1092-102; Ciotti P et al. Eur J Med Genet. 2009 May;52:311-4; Dollfus H et al. Invest. Ophthalmol. Vis. Sci. 2002 Sep;43:3067-74; Elli L et al. Am. J. Gastroenterol. 2006 Nov;101:2655-8; Wu P et al. J. Hum. Genet. 2012 Apr;57:238-43; Rothberg PG et al. Mol. Diagn. 2001 Mar;6:49-54; Park TY et al. Scand. J. Gastroenterol. 2015 Mar;50:360-7; Olschwang S et al. Hum. Mutat. 1998;12:424-30; Gallou C et al. Hum. Mutat. 2004 Sep;24:215-24; Corcos O et al. Pancreas. 2008 Jul;37:85-93. Several other alterations at the same codon (p.P86A, p.P86L, and p.P86R) have been reported in individuals with VHL (Nordstrom-O'Brien M et al. Hum. Mutat. 2010 May;31:521-37). In addition, based on both internal structural analysis and published structural analysis, this alteration is anticipated to result in a significant decrease in structural stability (Van Molle I et al. Chem. Biol. 2012 Oct;19:1300-12; Yuan P et al. Cancer Biol. Ther. 2016 Jun;17:599-603). Of note, this mutation is also designated as p.P157S (c.469C>T) in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Women's Health and 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 | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2022-06-22 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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: 7728151, 9829911, 11257211, 17024664, 19408298). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 178692). This variant is also known as 469C>T, Pro157Ser. This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 8634692, 9829912, 19464396, 27057652, 27527340). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 86 of the VHL protein (p.Pro86Ser). |
| Genomic Diagnostic Laboratory, |
RCV000155449 | SCV000264684 | pathogenic | Von Hippel-Lindau syndrome | 2016-02-26 | no assertion criteria provided | clinical testing |