Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000168239 | SCV000218908 | uncertain significance | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2023-06-19 | 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on VHL protein function. ClinVar contains an entry for this variant (Variation ID: 188263). This variant has not been reported in the literature in individuals affected with VHL-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 56 of the VHL protein (p.Ala56Val). |
| Ambry Genetics | RCV000219530 | SCV000273505 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-03-26 | criteria provided, single submitter | clinical testing | The c.167C>T (p.A56V) alteration is located in exon 1 (coding exon 1) of the VHL gene. This alteration results from a C to T substitution at nucleotide position 167, causing the alanine (A) at amino acid position 56 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Fulgent Genetics, |
RCV002485045 | SCV002779217 | uncertain significance | Chuvash polycythemia; Pheochromocytoma; Von Hippel-Lindau syndrome; Nonpapillary renal cell carcinoma | 2022-03-28 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV003995616 | SCV004832783 | uncertain significance | Von Hippel-Lindau syndrome | 2023-06-26 | criteria provided, single submitter | clinical testing | This missense variant replaces alanine with valine at codon 56 of the VHL protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with a non-metastatic Von Hippel-Lindau syndrome-associated pancreatic neuroendocrine tumor (PMID: 29748190). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |