ClinVar

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser365 amino acid residue in FH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12772087, 22243733, 22565324). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 429174). This missense change has been observed in individual(s) with clinical features of hereditary leiomyomatosis and renal cell cancer syndrome (PMID: 31831373; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with asparagine at codon 365 of the FH protein (p.Ser365Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine.