Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Genomic Diagnostic Laboratory, |
RCV000767239 | SCV000897782 | uncertain significance | Von Hippel-Lindau syndrome | 2018-08-01 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV004027205 | SCV005036780 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-02-19 | criteria provided, single submitter | clinical testing | The p.F76Y variant (also known as c.227T>A), located in coding exon 1 of the VHL gene, results from a T to A substitution at nucleotide position 227. The phenylalanine at codon 76 is replaced by tyrosine, an amino acid with highly similar properties. This variant has been observed in at least one individual with a personal and/or family history that is consistent with von Hippel-Lindau syndrome (Ambry internal data). Two other alterations at the same codon, p.F76I (c.226T>A) and p.F76L (c.226T>C), have been reported in multiple individuals with a personal history that is consistent with von Hippel-Lindau syndrome and have been shown to be destabilizing to the local structure based on internal structural analysis (Li C et al. Hum Mutat, 1998;Suppl 1:S31-3; Chen F et al. Hum Mutat, 1995;5:66-75; Gallou C et al. Hum Mutat, 1999;13:464-75; Zbar B et al. Hum Mutat, 1996;8:348-57; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly 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. |