ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.347T>G (p.Leu116Arg) (rs879254230)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236337 SCV000293915 uncertain significance not provided 2016-02-05 criteria provided, single submitter clinical testing This variant is denoted VHL c.347T>G at the cDNA level, p.Leu116Arg (L116R) at the protein level, and results in the change of a Leucine to an Arginine (CTT>CGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. VHL Leu116Arg 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 Leucine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. VHL Leu116Arg occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is located in the beta-domain and is involved in binding to CCT complex (Yuen 2009, UniProt). While computational modeling has predicted VHL Leu116Arg to be functionally significant (Rajasekaran 2008), in-house 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 Leu116Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000818505 SCV000959123 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 116 of the VHL protein (p.Leu116Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with VHL-related disease. ClinVar contains an entry for this variant (Variation ID: 246383). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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