ClinVar

Description

The p.C261F variant (also known as c.782G>T), located in coding exon 5 of the LDLR gene, results from a G to T substitution at nucleotide position 782. The cysteine at codon 261, located in LDLR class A repeat 6, is replaced by phenylalanine, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This particular cysteine alteration, also referred to as C240F, has been reported in individuals with hypercholesterolemia and in FH cohorts (Ekström U et al. Eur J Clin Invest. 1998;28:740-7; Leren TP et al. Semin Vasc Med. 2004;4:75-85; Brusgaard K et al. Clin Genet., 2006;69:277-83; Voevoda MI et al. Genetika. 2008;44(10):1374-8). This alteration was detected in compound heterozygosity with a second LDLR alteration in a proband with severe, early onset disease, and was seen alone in two affected relatives and one unaffected relative. In vitro studies indicated this variant resulted in impaired LDL uptake and degradation (Ekström U et al. Clin Genet. 1999;55:332-9). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 6 (Ambry internal data). 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 majority of available evidence to date, this variant is likely to be pathogenic.