ClinVar Genomic variation as it relates to human health

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. This variant disrupts the p.Arg160 amino acid residue in FH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15937070; Invitae). 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. This variant has not been reported in the literature in individuals affected with FH-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 160 of the FH protein (p.Arg160Thr).

The p.R160T variant (also known as c.479G>C), located in coding exon 4 of the FH gene, results from a G to C substitution at nucleotide position 479. The arginine at codon 160 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.