ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.463G>C (p.Val155Leu)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001323712 SCV001514639 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-07-03 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 155 of the VHL protein (p.Val155Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant also falls at the last nucleotide of exon 2 of the VHL coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with von Hippel-Lindau (VHL) syndrome (Invitae). 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: Benign; Align-GVGD: Class C2). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
GeneDx RCV001577162 SCV001804498 likely pathogenic not provided 2020-09-18 no assertion criteria provided clinical testing Variant at the last nucleotide of the exon in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed in large population cohorts (Lek 2016); Protein-based in silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29748190, 20233476, 15300849, 25525159, 21463266, 12202531)

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