Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001225655 | SCV001397940 | uncertain significance | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2023-05-30 | 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. Several studies have shown that the VHL protein created from a downstream methionine located at codon 54 is biologically active, and exhibits properties similar to the full-length, wild-type protein (PMID: 9671762, 9751722). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 953371). 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 creates a premature translational stop signal (p.Glu46Aspfs*78) in the VHL gene. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 54 has the potential to rescue this variant. |
| All of Us Research Program, |
RCV004004808 | SCV004833077 | uncertain significance | Von Hippel-Lindau syndrome | 2023-05-04 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV004032545 | SCV005036552 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-02-29 | criteria provided, single submitter | clinical testing | The c.138_160del23 variant, located in coding exon 1 of the VHL gene, results from a deletion of 23 nucleotides at nucleotide positions 138 to 160, causing a translational frameshift with a predicted alternate stop codon (p.E46Dfs*78). Premature stop codons are typically deleterious in nature; however, an alternate initiation codon exists downstream of this alteration, and is reported to result in a biologically active isoform, known as VHL19 (Schoenfeld A et al. Proc. Natl. Acad. Sci. U.S.A. 1998 Jul; 95(15):8817-22; Iliopoulos O et al. Proc. Natl. Acad. Sci. U.S.A. 1998 Sep; 95(20):11661-6). Based on the available evidence, the clinical significance of this alteration remains unclear. |