Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000590057 | SCV000697483 | uncertain significance | not provided | 2016-10-27 | criteria provided, single submitter | clinical testing | Variant summary: The VHL c.227T>C (p.Phe76Cys) variant causes a missense change involving a highly conserved nucleotide with 4/4 in silico tools predicting a deleterious outcome, although these predictions have yet to be functionally assessed. This variant has not been observed in controls (ExAC, 1000 Gs, or ESP), nor has it been, to our knowledge, reported in affected individuals via publications or cited by a reputable databases/clinical. Other alterations of the same codon, F76S, F76I and F76L have been reported in VHL pts. Due to the absence of clinical information and lack of functional studies, the variant has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available. |
| Labcorp Genetics |
RCV001209996 | SCV001381459 | uncertain significance | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2021-08-06 | criteria provided, single submitter | clinical testing | 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. This variant disrupts the p.Phe76 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12114495, 17661816, 20064270, 23632291, 27439424). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with VHL-related conditions. ClinVar contains an entry for this variant (Variation ID: 496051). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with cysteine at codon 76 of the VHL protein (p.Phe76Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. |
| Ambry Genetics | RCV002448821 | SCV002734686 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-11-04 | criteria provided, single submitter | clinical testing | The p.F76C variant (also known as c.227T>G), located in coding exon 1 of the VHL gene, results from a T to G substitution at nucleotide position 227. The phenylalanine at codon 76 is replaced by cysteine, an amino acid with highly dissimilar properties. Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data). 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. |