ClinVar

Description

This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 28964736, Invitae). ClinVar contains an entry for this variant (Variation ID: 977987). This variant disrupts the p.Cys340 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 23535506, 20809525, 30592178), which suggests that this may be a clinically significant amino acid residue. 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 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is present in population databases (rs755757866, ExAC 0.006%). This sequence change replaces cysteine with phenylalanine at codon 340 of the LDLR protein (p.Cys340Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine.