Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000589290 | SCV000697514 | pathogenic | Hereditary cancer-predisposing syndrome | 2016-02-10 | criteria provided, single submitter | clinical testing | Variant summary: VHL c.407T>G variant affects a conserved nucleotide, resulting in amino acid change from an aromatic Phe to a medium sized polar Cys. 4/4 in-silico tools predict damaging outcome for this variant (Mutation Taster not captured due to low p-value). Hif1-alpha regulation has been strongly correlated with hemangioblastoma susceptibility; and functional studies have shown that F136C disrupts binding to Hif1-alpha and elongin C, and reduces binding affinity for TBP-1 (Corn_NG_2003). This variant is not found in 121412 control chromosomes; however, it has been cited in at least 5 patients with pheochromocytoma and 1 patient with haemangioblastoma of the CNS. Taken together, this is a disease variant and was classified as pathogenic. |
| Genomic Diagnostic Laboratory, |
RCV000767268 | SCV000897819 | uncertain significance | Von Hippel-Lindau syndrome | 2018-08-01 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000589290 | SCV002632633 | uncertain significance | Hereditary cancer-predisposing syndrome | 2017-02-02 | criteria provided, single submitter | clinical testing | The p.F136V variant (also known as c.407T>G), located in coding exon 2 of the VHL gene, results from a T to G substitution at nucleotide position 407. The phenylalanine at codon 136 is replaced by valine, an amino acid with highly similar properties. Although this specific amino acid change has not been reported in the literature, two other alterations at this same codon, p.F136S and p.F136C, have been reported in individuals with von Hippel-Lindau syndrome (Whaley JM et al. Am. J. Hum. Genet., 1994 Dec;55:1092-102; Crossey PA et al. Hum. Mol. Genet., 1994 Aug;3:1303-8). 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. |