ClinVar

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies using patient's cells have shown that disruption of Met54 (p.Met54Ile) affects VHLp19 expression, but does not affect VHLp30 expression (PMID: 26224408). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on VHL protein function. Disruption of the initiator Met54 codon (p.Met54Ile) has been observed to be homozygous in individuals of Moroccan origin who were affected with erythrocytosis and pulmonary arterial hypertension, and reported to segregate with erythrocytosis in a family (PMID: 26224408, 27578599). However, individuals observed to be heterozygous did not present von Hippel-Lindau (VHL) associated clinical features (PMID: 26224408), suggesting that its association with VHL is currently unclear. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the VHL mRNA at codon 54 (Met54), which is responsible for translation initiation of the VHLp19 functional isoform. However, the initiator methionine at codon 1 (Met1) responsible for translation initiation of the VHLp30 functional isoform is preserved.