ClinVar Genomic variation as it relates to human health

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 231 of the LDLR protein (p.Cys231Arg). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys231 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 8664907, 10782930, 20809525), which suggests that this may be a clinically significant amino acid residue. 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). Experimental studies have shown that this missense change affects LDLR function (PMID: 19073363). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 251396). This variant is also known as C210R. This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 19073363, 27830735). It has also been observed to segregate with disease in related individuals.

The p.C231R pathogenic mutation (also known as c.691T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at nucleotide position 691. The cysteine at codon 231 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, which is also known as p.C210R, has been reported as homozygous in an individual with FH, being passed down from his affected parents (Wang L et al. Nutr Metab Cardiovasc Dis, 2009 Jul;19:391-400). This alteration has also been detected in FH cohorts (Defesche JC et al. J Clin Lipidol Sep;11:1338-1346.e7; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 5 (Ambry internal data). Another alteration at the same codon, p.C231G (c.691T>G), has been described in multiple individuals with FH, and has been reported as commonly occurring in Norwegian FH cohorts (Sundvold H et al. Hum Mutat. 1996;7:70-1; Heath KE et al. Eur J Hum Genet. 2001;9:244-52; Dušková L et al. Atherosclerosis. 2011;216:139-45; Tichý L et al. Atherosclerosis. 2012;223(2):401-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies using flow cytometry analysis demonstrate low LDL binding and internalization ability (PMID: 19073363); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as C210R; This variant is associated with the following publications: (PMID: 2988123, 12459547, 31447099, 34037665, 19073363)

This missense variant replaces cysteine with arginine at codon 231 in the LDLR type A repeat 5 of the LDLR protein. This variant is also known as p.Cys210Arg in the mature protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. An in vitro functional study has shown that this variant causes an approximately 40% reduction in LDLR binding and uptake (PMID: 19073363). This LDLR variant has been reported in three heterozygous individuals affected with familial hypercholesterolemia (PMID: 28964736, 34037665; ClinVar SCV001432574.1). This variant has also been observed in homozygous state in one individual affected with severe homozygous familial hypercholesterolemia (PMID: 19073363). It has been shown that this variant segregates with disease in three affected individuals in one family (PMID: 19073363). Different variants affecting the same codon, p.Cys231Gly and p.Cys231Trp, are considered to be disease-causing (ClinVar variation ID: 251397, 251400), suggesting that cysteine at this position is important for LDLR protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

The LDLR c.691T>C variant is predicted to result in the amino acid substitution p.Cys231Arg. This amino acid position is also referred to as p.Cys210 using legacy nomenclature. This variant has been reported in the heterozygous and homozygous states in multiple individuals with hypercholesterolemia (Table 1, Wang et al. 2009. PubMed ID: 19073363; Table S2, Defesche et al. 2017. PubMed ID: 28964736; Table S1, Sturm et al. 2021. PubMed ID: 34037665). This variant has not been reported in a large population database, indicating this variant is rare. Alternate nucleotide substitutions affecting the same amino acid (p.Cys231Trp, p.Cys231Gly, and p.Cys231Tyr) have been reported in many individuals with hypercholesterolemia (Table 3, Marduel et al. 2010. PubMed ID: 20809525; Sundvold et al. 1996. PubMed ID: 8664907; Table 1, Shin et al. 2000. PubMed ID: 10782930). The c.691T>C (p.Cys231Arg) variant is interpreted as pathogenic.