ClinVar

Description

The p.H656N variant (also known as c.1966C>A), located in coding exon 13 of the LDLR gene, results from a C to A substitution at nucleotide position 1966. The histidine at codon 656 is replaced by asparagine, an amino acid with similar properties, and is located in the EGF precursor-like domain. This variant, also referred to as p.H635N, has been reported in unrelated individuals reported to have familial hypercholesterolemia (Mozas P et al. Hum Mutat. 2004:24(2):187; Damgaard D et al. Atherosclerosis. 2005;180(1):155-60; van der Graaf A et al. Circulation. 2011;123(11):1167-73; Bertolini S et al. Atherosclerosis. 2013;227(2):342-8). This variant was also reported in a myocardial infarction-free control group, though clinical details were limited (Do R et al. Nature. 2015;518(7537):102-6). A study using surface plasmon resonance spectroscopy showed that this variant results in altered binding for substrate at low pH (Lo Surdo P et al. EMBO Rep. 2011;12(12):1300-5). In addition, another alteration affecting this amino acid (p.H656Q, c.1968C>G) has been reported in association with hypercholesterolemia (Descamps OS et al. Eur J Clin Invest. 2001;31(11):958-65 (reported as p.H635Q)). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. Based on data from ExAC, the A allele has an overall frequency of <0.01% (2/106164). 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.