ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.463+2T>C (rs5030814)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000690034 SCV000817710 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-06-05 criteria provided, single submitter clinical testing This sequence change affects a donor 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 reported in an individual with a personal and family history of von Hippel-Lindau syndrome (PMID: 8707293). This variant is also known as 676+2 C>T in the literature. 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. This donor splice site variant lies upstream of exon 3 sequence encoding the elongin C binding domain of VHL, which is required for protein stability and tumor suppressive activity (PMID: 9447969, 10900011, 14987375). Variants that disrupt this domain have been determined to be pathogenic (PMID: 9452032, 9829912, 17350623, 19602254, 25371412). This suggests that this region is critical for VHL protein function, and that other variants that disrupt this region may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
MutSpliceDB: a database of splice sites variants effects on splicing,NIH RCV000786844 SCV000925741 not provided not provided no assertion provided in vitro

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