ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.320G>C (p.Arg107Pro) (rs193922609)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492682 SCV000580967 pathogenic Hereditary cancer-predisposing syndrome 2016-02-02 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,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000030583 SCV000264705 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing
GeneDx RCV000486047 SCV000565655 likely pathogenic not provided 2016-09-12 criteria provided, single submitter clinical testing This variant is denoted VHL c.320G>C at the cDNA level, p.Arg107Pro (R107P) at the protein level, and results in the change of an Arginine to a Proline (CGC>CCC). This variant has been identified in at least two families with von Hippel-Lindau (VHL) disease (Stolle 1998, Rocha 2003). VHL Arg107Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. VHL Arg107Pro occurs at a position that is conserved across species and is located in the beta domain and the region involved in binding to CCT complex (Yuen 2009, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider VHL Arg107Pro to be a likely pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000030583 SCV000053259 likely pathogenic Von Hippel-Lindau syndrome 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Invitae RCV000816283 SCV000956784 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-09-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 107 of the VHL protein (p.Arg107Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in families affected with von Hippel-Lindau (VHL) syndrome (PMID: 9829911, 12624160). This variant is also known as 533G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 36900). 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.Arg107 amino acid residue in VHL. Other variants that disrupt this residue have been observed in affected individuals (PMID: 19336503, 21362373, 22799452), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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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