ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.460C>T (p.Pro154Ser) (rs1553619993)

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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 RCV000566330 SCV000675816 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-18 criteria provided, single submitter clinical testing The p.P154S variant (also known as c.460C>T), located in coding exon 2 of the VHL gene, results from a C to T substitution at nucleotide position 460. The proline at codon 154 is replaced by serine, an amino acid with similar properties. This alteration has been reported in a father and son with isolated pheochromocytoma and was not detected in his two unaffected children (Takahashi K et al. Intern. Med. 2006; 45(5):265-9). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 12000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001046833 SCV001210751 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-10-01 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 154 of the VHL protein (p.Pro154Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with von Hippel-Lindau syndrome in a family (PMID: 16595991). It has also been reported in an individual referred for paraganglioma-pheochromocytoma genetic testing (PMID: 22517557). ClinVar contains an entry for this variant (Variation ID: 486714). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Pro154 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 20660572, 23143947, 7987306, 25867206, 17024664, 8956040), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001420952 SCV001623426 pathogenic Von Hippel-Lindau syndrome 2021-05-12 criteria provided, single submitter clinical testing Variant summary: VHL c.460C>T (p.Pro154Ser) results in a non-conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta/alpha domain (IPR022772) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251494 control chromosomes. c.460C>T has been reported in the literature in individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (e.g. Takahashi_2006, van Nederveen_2009, Wong_2016), including multiple individuals in a family in which the variant co-segregated with disease (e.g. Takahashi_2006). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) have cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.

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