Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000236061 | SCV000293889 | uncertain significance | not provided | 2022-09-29 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge |
| Labcorp Genetics |
RCV000537589 | SCV000626911 | uncertain significance | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2023-10-29 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 193 of the VHL protein (p.Asn193Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with VHL-related conditions. ClinVar contains an entry for this variant (Variation ID: 246368). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. |
| Ambry Genetics | RCV001024530 | SCV001186561 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-09-14 | criteria provided, single submitter | clinical testing | The p.N193S variant (also known as c.578A>G), located in coding exon 3 of the VHL gene, results from an A to G substitution at nucleotide position 578. The asparagine at codon 193 is replaced by serine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| All of Us Research Program, |
RCV003998924 | SCV004821740 | uncertain significance | Von Hippel-Lindau syndrome | 2023-02-24 | criteria provided, single submitter | clinical testing | This missense variant replaces asparagine with serine at codon 193 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 affected with endometrial cancer who may have a pathogenic covariant (PMID: 34994648). 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. |
| Baylor Genetics | RCV004567785 | SCV005055796 | uncertain significance | Chuvash polycythemia | 2024-02-13 | criteria provided, single submitter | clinical testing |