ClinVar

Description

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 183 of the VHL protein (p.Ser183Leu). This variant is present in population databases (rs5030823, gnomAD 0.0009%). This missense change has been observed in individual(s) with erythrocytosis, pulmonary arterial hypertension (PAH) and/or paraganglioma (PMID: 21454469, 24466223). ClinVar contains an entry for this variant (Variation ID: 411985). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects VHL function (PMID: 21454469, 30338240). This variant disrupts the p. Ser183 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 24466223; Invitae), which suggests that this may be a clinically significant amino acid residue. 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.