ClinVar

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys184 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9678702, 11668627, 20236128, 20828696, 25461735). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 251294). This variant is also known as Cys163Arg. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9484998, 30592178, 32331935). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 184 of the LDLR protein (p.Cys184Arg).