ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.422dup (p.Asn141fs)

dbSNP: rs1553619976
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen VHL Variant Curation Expert Panel, ClinGen RCV004691237 SCV005187288 pathogenic Von Hippel-Lindau syndrome 2024-06-25 reviewed by expert panel curation The NM_000551.4(VHL):c.422dup (p.Asn141fs) is a frameshift variant affecting position 141. This variant is not expected to undergo nonsense mediated decay, but is in a functional domain critical to the protein function (nuclear export domain) (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Two commercial laboratories report cases. Case 1 (0.5 points): displayed bilateral renal masses and likely pheochromocytoma, with a small Paraganglioma panel run. Case 2 (0.5): Multiple renal tumors in 40s, no other family history known, and a 13-gene panel was run for renal cancers (PS4_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024).
Labcorp Genetics (formerly Invitae), Labcorp RCV000474557 SCV000553408 pathogenic Chuvash polycythemia; Von Hippel-Lindau syndrome 2016-04-01 criteria provided, single submitter clinical testing 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. 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 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.
Ambry Genetics RCV000564069 SCV000664528 pathogenic Hereditary cancer-predisposing syndrome 2016-12-13 criteria provided, single submitter clinical testing The c.422dupA variant, located in coding exon 2 of the VHL gene, results from a duplication of A at nucleotide position 422, causing a translational frameshift with a predicted alternate stop codon (p.N141Kfs*3). This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.

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