Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001327637 | SCV001518722 | uncertain significance | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2020-01-13 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 122 of the VHL protein (p.Ala122Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in an individual with clinical features of von Hippel-Lindau syndrome (Invitae). |
| Ambry Genetics | RCV002456464 | SCV002617651 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-10-31 | criteria provided, single submitter | clinical testing | The c.365C>T variant (also known as p.A122V), located in coding exon 2 of the VHL gene, results from a C to T substitution at nucleotide position 365. The alanine at codon 122 is replaced by valine, an amino acid with similar properties. This alteration has been observed in individuals with a personal and/or family history that is consistent with VHL-related disease (Ambry internal data; Favier J et al. Mod Pathol, 2020 01;33:57-64). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive and direct evidence is insufficient at this time (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |