ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.422dup (p.Asn141fs) (rs1553619976)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564069 SCV000664528 pathogenic Hereditary cancer-predisposing syndrome 2016-12-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000474557 SCV000553408 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2016-04-01 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 2 of the VHL mRNA (c.422dupA), causing a frameshift at codon 141. This creates a premature translational stop signal within the last 15 amino acids of the penultimate exon of the VHL mRNA (p.Asn141Lysfs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated VHL protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a VHL-related disease. This truncation deletes the VHL elongin binding domain encoded by exon 3 (PMID: 14987375). This domain is required for protein stability and tumor suppressive activity (PMID: 10900011). Deletions of exon 3 have been reported in multiple families with von Hippel-Landau Syndrome (PMID: 19280651, 8069305, 8707293). For these reasons, this variant has been classified as Pathogenic.

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