ClinVar

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 126 of the VHL protein (p.Asp126Asn). This variant is present in population databases (rs104893831, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive erythrocytosis and pulmonary hypertension, and/or polycythemia and pulmonary hypertension (PMID: 21454469, 30338240, 35734542). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with clinical features of autosomal dominant von Hippel-Lindau syndrome, as well as in unaffected individuals (Invitae; external communication); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 141044). 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). In summary, this variant has been classified as Pathogenic for autosomal recessive erythrocytosis. However, the risk conferred by this variant is uncertain for autosomal dominant von Hippel-Lindau syndrome.