ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.575C>G (p.Pro192Arg) (rs902694906)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001024492 SCV001186515 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-08 criteria provided, single submitter clinical testing The p.P192R variant (also known as c.575C>G), located in coding exon 3 of the VHL gene, results from a C to G substitution at nucleotide position 575. The proline at codon 192 is replaced by arginine, an amino acid with dissimilar properties. Another alteration at this same codon, p.P192L, has been described in multiple patients affected with pheochromocytomas (Ambry internal data; Neumann HPH et al. JAMA Netw Open, 2019 08;2:e198898). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001294333 SCV001483206 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-03-09 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 192 of the VHL protein (p.Pro192Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of von Hippel-Lindau syndrome (PMID: 19558618, Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Pro192 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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