ClinVar Genomic variation as it relates to human health

The c.589T>C (p.Cys197Arg) variant of the LDLR gene has been identified in heterozygous status in at least eight unrelated individuals who fulfill the clinical criteria of Familial Hypercholesterolemia (FH) (PMID: 9026534, 19446849, 22883975, 35929461, 32331935, 31491741, 23375686). This variant has also been reported in homozygous status in an individual with FH (PMID: 17094996). In-silico computational prediction tools suggest that the p.Cys197Arg variant may have deleterious effect on the protein function (REVEL score: 0.91). This variant affects one of the sixty highly conserved cysteine residues located within an LDLR class A 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). This variant is found to be rare (1/251216; 0.00039%) in the general population database (gnomAD) and interpreted as likely pathogenic/pathogenic by several submitters in the ClinVar database (ClinVar ID: 183091). Other amino acid substitutions at the same codon (p.Cys197Gly, p.Cys197Phe, p.Cys197Trp) have been classified as likely pathogenic by several ClinVar submitters including the Clingen Familial Hypercholesterolemia variant curation expert panel (ClinVar ID: 251309, 251308, 251311). Therefore, the c.589T>C (p.Cys197Arg) variant in the LDLR gene is classified as likely pathogenic.

0/190 non-FH alleles

This variant disrupts the p.Cys197 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 18096825, 20538126, 21276076, 23064986, 27765764, 27816806). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. 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: 183091). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 23375686, 32331935). This variant is present in population databases (rs730882085, gnomAD 0.0009%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 197 of the LDLR protein (p.Cys197Arg).

This missense variant replaces cysteine with arginine at codon 197 of the LDLR protein. This variant is described as p.Cys176Arg in the mature protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897) and is expected to have deleterious impact on the LDLR protein folding and stability. Functional studies have shown that this variant causes a significant defect in LDLR protein function and post-translation protein maturation (PMID: 25647241). This variant has been reported in heterozygous individuals affected with familial hypercholesterolemia (PMID: 19446849, 22883975) and in an individual affected with homozygous familial hypercholesterolemia (PMID: 9026534). This variant has been identified in 1/251216 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position (p.Cys197Gly, p.Cys197Phe, p.Cys197Trp and p.Cys197Tyr) are known to be disease-causing (ClinVar variation ID: 251308, 251309, 251311, 200919), indicating that cysteine at this position is important for LDLR function. Based on the available evidence, this variant is classified as Pathogenic.

The p.C197R pathogenic mutation (also known as c.589T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at nucleotide position 589. The cysteine at codon, located in LDLR class A repeat 5, 197 is replaced by arginine, 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 alteration has been reported in FH individuals (Webb JC et al. J. Lipid Res., 1996 Feb;37:368-81; Guardamagna O et al. J. Pediatr., 2009 Aug;155:199-204.e2; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4), and was suggested to reduced LDL binding (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 5. In addition, alterations affecting the same amino acid (C197Y, C197W, C197G, C197F) have also been described in FH (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Chmara M et al. J Appl Genet. 2010;51(1):95-106; Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.