ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.555C>G (p.Tyr185Ter) (rs864622109)

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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 RCV000219064 SCV000274604 pathogenic Hereditary cancer-predisposing syndrome 2019-09-22 criteria provided, single submitter clinical testing The p.Y185* pathogenic mutation (also known as c.555C>G), located in coding exon 3 of the VHL gene, results from a C to G substitution at nucleotide position 555. This changes the amino acid from a tyrosine to a stop codon within coding exon 3. This mutation has been detected in multiple VHL patients (Crossey PA et al. Hum. Mol. Genet. 1994 Aug;3(8):1303-8; Zbar B et al. Hum. Mutat. 1996;8(4):348-57; Stolle C et al. Hum. Mutat. 1998;12(6):417-23). In addition, this mutation was detected as a somatic mutation in a primary sporadic renal cell cancer (Whaley JM et al. Am. J. Hum. Genet. 1994 Dec;55(6):1092-102). Of note, this alteration has also been designated as 768C>G and Tyr256Ter in published literature. In addition to the clinical data presented in the literature, 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.
Invitae RCV001377065 SCV001574297 likely pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-02-08 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the VHL gene (p.Tyr185*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acids of the VHL protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with von Hippel-Lindau disease (PMID: 23298237, 7987306). This variant is also known as Tyr256Ter in the literature. ClinVar contains an entry for this variant (Variation ID: 223233). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Leu188 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7563486, 8772572, 7987306, 23772956, 19228690). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000208826 SCV000264771 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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