Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000492124 | SCV000580962 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2016-04-13 | criteria provided, single submitter | clinical testing | The p.S72P variant (also known as c.214T>C), located in coding exon 1 of the VHL gene, results from a T to C substitution at nucleotide position 214. The serine at codon 72 is replaced by proline, an amino acid with similar properties. This variant was reported in two suspected VHL families with clinical features including retinal angioma and cerebellar hemangioblastoma (Ong KR et al. Hum. Mutat. 2007 Feb; 28(2):143-9). It was also reported in an Indian female diagnosed with VHL, who had multi-cystic pancreatic lesions, central nervous system hemangioblastoma, and a family history of VHL (Vikkath N et al. Fam. Cancer 2015 Dec; 14(4):585-94). In one functional study, this alteration's interactions with hypoxia inducible factors (HIF), which affect protein stability, were similar to that of a known VHL mutant (Rechsteiner MP et al. Cancer Res. 2011 Aug; 71(16):5500-11). 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 6375 samples (12750 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.02% (greater than 12000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV001382227 | SCV001580899 | pathogenic | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2020-12-01 | criteria provided, single submitter | clinical testing | Experimental studies have shown that this variant affects VHL protein function (PMID: 21715564). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function. This variant has been observed in individual(s) with von Hippel Lindau syndrome (PMID: 17024664, 25952756, Invitae). ClinVar contains an entry for this variant (Variation ID: 223163). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with proline at codon 72 of the VHL protein (p.Ser72Pro). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and proline. |
| Genomic Diagnostic Laboratory, |
RCV000208787 | SCV000264672 | likely pathogenic | Von Hippel-Lindau syndrome | 2016-02-26 | no assertion criteria provided | clinical testing |