ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.464-2A>G (rs5030816)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216737 SCV000273653 pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Well-characterized mutation at same position
Invitae RCV000824251 SCV000965141 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in the last intron (intron 2) of the VHL gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with von Hippel-Lindau disease (PMID: 8707293). This variant is also known as 677-2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 223222). 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. For these reasons, this variant has been classified as Pathogenic.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000208810 SCV000264750 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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