Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000662559 | SCV000785158 | uncertain significance | Von Hippel-Lindau syndrome | 2017-05-10 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001372824 | SCV001569514 | uncertain significance | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2023-12-03 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Glu10*) 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 premature translational stop signal has been observed in individual(s) with congenital erythrocytosis (PMID: 24115288). ClinVar contains an entry for this variant (Variation ID: 548745). 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. |
| Ambry Genetics | RCV003303094 | SCV003999525 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-05-10 | criteria provided, single submitter | clinical testing | The p.E10* variant (also known as c.28G>T), located in coding exon 1 of the VHL gene, results from a G to T substitution at nucleotide position 28. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. This alteration was identified as heterozygous in a patient from France with congenital erythrocytosis (Bento C et al. Hum Mutat, 2014 Jan;35:15-26). Premature stop codons are typically deleterious in nature; however, an alternate initiation codon exists 44 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. |
| All of Us Research Program, |
RCV000662559 | SCV004842742 | uncertain significance | Von Hippel-Lindau syndrome | 2023-12-13 | criteria provided, single submitter | clinical testing | This variant changes 1 nucleotide in exon 1 of the VHL gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. However, there is a naturally occurring VHL protein isoform that has start of translation at methionine 54 and appears to retain tumor suppressor activity (PMID: 9671762, 9751722, 10102622), which may ameliorate the deleterious effects of this N-terminal frameshift. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with congenital erythrocytosis (PMID: 24115288). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of VHL function is a known mechanism of disease (clinicalgenome.org). 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. |