ClinVar Genomic variation as it relates to human health

The NM_000527.5(LDLR):c.479G>A (p.Cys160Tyr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL=0.936. PM1: Variant meets PM2, is a missense in exon 4, and alters Cys160, one of the cysteine residues listed.

This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Hypercholesterolemia, familial, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product.

The p.C160Y pathogenic mutation (also known as c.479G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 479. The cysteine at codon 160, located in LDLR class A repeat 4, 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 change, also referred to as p.C139Y, has been detected in FH cohorts (Day IN et al. Hum. Mutat., 1997;10:116-27; Santos PC et al. Atherosclerosis, 2014 Mar;233:206-10; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7). Other variants affecting this codon (p.C160R, p.C160G, and p.C160F) have also been detected in FH cohorts (Amsellem S et al. Hum. Genet., 2002 Dec;111:501-10; Yu W et al. Atherosclerosis, 2002 Dec;165:335-42; Chakir Kh et al. Mol. Genet. Metab., 1998 Jan;63:31-4; Bourbon M et al. Atherosclerosis, 2017 07;262:8-13). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 4 (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.