ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 233 of the FH protein (p.Arg233Leu). This variant is present in population databases (rs121913123, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of hereditary leiomyomatosis and renal cell cancer (PMID: 12772087, 29423582; Invitae). This variant is also known as c.569G>T, p.Arg190Leu. ClinVar contains an entry for this variant (Variation ID: 16237). 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 FH protein function. This variant disrupts the p.Arg233 amino acid residue in FH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12772087, 15937070, 21398687; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.