Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000532705 | SCV000626922 | uncertain significance | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2023-07-16 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 456598). This sequence change creates a premature translational stop signal (p.Glu31*) 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. 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. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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). 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. |
| Counsyl | RCV000576425 | SCV000677842 | uncertain significance | Von Hippel-Lindau syndrome | 2017-05-10 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV003343894 | SCV004066703 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-09-08 | criteria provided, single submitter | clinical testing | The p.E31* variant (also known as c.91G>T), located in coding exon 1 of the VHL gene, results from a G to T substitution at nucleotide position 91. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. The predicted stop codon occurs in the 5’ end of theVHL gene. Premature stop codons are typically deleterious in nature; however, an alternate initiation codon exists 23 residues downstream from 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). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |