ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.613C>T (p.Arg205Cys) (rs199926195)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481600 SCV000571021 uncertain significance not provided 2016-07-15 criteria provided, single submitter clinical testing This variant is denoted VHL c.613C>T at the cDNA level, p.Arg205Cys (R205C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has not, to our knowledge, been published in the literature as a germline variant; however,it has been reported as a somatic variant in endometrial carcinoma according to the Catalogue of Somatic Mutations in Cancer (COSMIC) database. VHL Arg205Cys was not observed at a significant allele frequency in 1000 Genomes. Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. VHL Arg205Cys occurs at a position that is not conserved and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether VHL Arg205Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000471333 SCV000553403 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-08-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 205 of the VHL protein (p.Arg205Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs199926195, ExAC 0.01%) but has not been reported in the literature in individuals with a VHL-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C25"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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