Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000216720 | SCV000273215 | pathogenic | Hereditary cancer-predisposing syndrome | 2015-01-02 | criteria provided, single submitter | clinical testing | The p.V84L pathogenic mutation (also known as c.250G>C and p.V155L), located in coding exon 1 of the VHL gene, results from a G to C substitution at nucleotide position 250. The valine at codon 84 is replaced by leucine, an amino acid with highly similar properties. This variant has been reported in apparent de novo transmission in one individual with pheochromocytoma, out of a cohort of 426 unrelated individuals presenting with clinical suspicion for VHL (Leonardi E et al. Ann. Hum. Genet. 2011 Jul; 75(4):483-96). Additionally, a well described mutation at the same position (c.250G>T), also resulting in the valine at codon 84 being replaced by leucine, has been identified in a number of families with early-onset pheochromocytomas (VHL type 2C) (Crossey PA et al. J. Med. Genet.1995 Nov; 32(11):885-6; Abbott MA et al. Am. J. Med. Genet. A 2006 Apr; 140(7):685-90). Based on the available evidence, p.V84L is classified as a pathogenic mutation. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000588802 | SCV000697488 | pathogenic | Von Hippel-Lindau syndrome | 2016-01-29 | criteria provided, single submitter | clinical testing | Variant summary: This c.250G>C variant affects a conserved nucleotide, resulting in amino acid change from Val to Leu in beta domain of VHL protein. 2/4 in-silico tools predict this variant to be damaging. This variant was not found in approximately 99326 chromosomes from ExAC. This variant has been reported in one VHL patient as a de novo occurrence (Leonardi_2011) and in other two VHL patients as somatic occurrence (Burnichon_2011, Pena-Llopis_2013). Another nucleotide change c.250G>T leading to the same amino acid change is a known pathogenic variant, strongly supporting that this nucleotide change is also pathogenic. Functional studies show that p.V84L mutant impairs in forming stable pVHL-ElonginC-ElonginB (VCB) complexes which is implicated in the disease (Knauth_2009). Taken together, this variant has been classified as a Pathogenic. |
| Genomic Diagnostic Laboratory, |
RCV000588802 | SCV000897790 | pathogenic | Von Hippel-Lindau syndrome | 2018-08-01 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001382229 | SCV001580901 | pathogenic | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2023-03-26 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on VHL function (PMID: 11331612, 11331613, 12510195, 19228690, 19602254, 21791076). 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) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function. ClinVar contains an entry for this variant (Variation ID: 229860). This missense change has been observed in individual(s) with von Hippel-Lindau syndrome (PMID: 8592333, 11409863, 16502427, 19215943, 19270817, 25078357). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 84 of the VHL protein (p.Val84Leu). |