ClinVar Genomic variation as it relates to human health

This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 23375686, 26081744). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys134 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10735632, 10978268, 11462246, 12730724, 18718593, 25921077). 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). 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 LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 251203). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 134 of the LDLR protein (p.Cys134Tyr).

The p.C134Y pathogenic mutation (also known as c.401G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 401. The cysteine at codon 134 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the ligand binding 3 domain. This alteration has been detected in an individual from an autosomal dominant hypercholesterolemia cohort (Bertolini S et al. Atherosclerosis. 2013;227:342-8). Internal structural analysis indicates this alteration would disrupt a disulfide bond needed for proper protein function (Mayhew Mn et al. Protein Eng. 1992;5(6):489-94; Daly NL et al. Proc Natl Acad Sci USA. 1995;92(14):6334-8; Fisher C et al. Mol Cell. 2006;22(2):277-83). In addition, other alterations at the same amino acid position, C134F, C134R and C134W, have also been detected in individuals from familial hypercholesterolemia cohorts (Lombardi MP et al. Clin Genet. 2000;57:116-24; Bertolini S et al. Arterioscler. Thromb Vasc Biol. 2000;20:E41-52). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in a family with hypercholesterolemia in published literature (Bertolini et al., 2013); This variant is associated with the following publications: (PMID: 2988123, 12459547, 23375686)