Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000492675 | SCV000580964 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-08-31 | criteria provided, single submitter | clinical testing | The p.S111R pathogenic mutation (also known as c.333C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at nucleotide position 333. The serine at codon 111 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in multiple individuals who meet established diagnostic criteria for Von Hippel-Lindau (VHL) syndrome (Chen F et al. Hum. Mutat. 1995 ; 5(1):66-75; Cybulski C et al. J. Med. Genet. 2002 Jul; 39(7):E38; Ambry internal data). Functional analysis indicates the serine at codon 111 is a critical phosphorylation residue, and is involved in regulation of cell cycle progression after DNA damage (Roe JS et al. Cell Cycle, 2011 Nov;10:3920-8). Based on internal structural assessment, this alteration targets a critical HIF-1 binding residue and impairs binding of the hydroxylated HIF-1α peptide (Hon WC et al. Nature, 2002 Jun;417:975-8; Min JH et al. Science, 2002 Jun;296:1886-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Invitae | RCV001204150 | SCV001375343 | pathogenic | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2023-10-09 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 111 of the VHL protein (p.Ser111Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 7728151, 12114495, 16868829, 25562111; Invitae). This variant is also known as 546C>A. ClinVar contains an entry for this variant (Variation ID: 223187). 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. Experimental studies have shown that this missense change affects VHL function (PMID: 22071692). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. |
| Genomic Diagnostic Laboratory, |
RCV000208866 | SCV000264709 | likely pathogenic | Von Hippel-Lindau syndrome | 2016-02-26 | no assertion criteria provided | clinical testing |