ClinVar

Description

The p.C143Y pathogenic mutation (also known as c.428G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 428. The cysteine at codon 143, located in LDLR class A repeat 3, is replaced by tyrosine, 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 C122Y) has been detected in individuals reported to have FH (Genschel J et al. Hum Mutat, 2001 Apr;17:354; Dedoussis GV et al. Hum Mutat, 2004 Mar;23:285-6; Wang L et al. Nutr Metab Cardiovasc Dis, 2009 Jul;19:391-400; Kim HN et al. Chonnam Med J, 2018 Jan;54:31-35). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 3 (Ambry internal data). This variant was reported to result in defective LDLR binding ability in one in vitro study (Wang L et al. Nutr Metab Cardiovasc Dis, 2009 Jul;19:391-400). In addition, another alteration affecting this codon (p.C143F, c.428G>T) has also been reported in association with FH Gomez A et al. Atherosclerosis, 2019 12;291:44-51). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.