ClinVar Genomic variation as it relates to human health

Variant summary: LDLR c.591C>G (p.Cys197Trp) results in a non-conservative amino acid change located in the 5th Low-density lipoprotein (LDL) receptor class A repeat (IPR002172) of the encoded protein sequence. This alters a highly conserved amino acid (HGMD) in which several other missense variants have been classified as pathogenic/likely pathogenic in ClinVar. Five of five in-silico tools predict a damaging effect of the variant on protein function, and a reported simulation predicts this residue to be a hotspot in which missense variants are likely to compromise conformational stability (Angarica_2016). The variant was absent in 251200 control chromosomes. c.591C>G has been reported in the literature in individuals affected with Hypercholesterolemia (Chmara_2010, Mickiewicz_2020, Sturm_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys197 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 20809525, 27816806, 24507775, 9026534, Invitae), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individuals affected with familial hypercholesterolemia (PMID: 20145306, Invitae). ClinVar contains an entry for this variant (Variation ID: 251311). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tryptophan at codon 197 of the LDLR protein (p.Cys197Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan.

The p.C197W variant (also known as c.591C>G and p.C176W), located in coding exon 4 of the LDLR gene , results from a C to G substitution at nucleotide position 591. The cysteine at codon 197, located in LDLR class A repeat 5, is replaced by tryptophan, 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 alteration has been reported in association with FH (Chmara M et al. J Appl Genet. 2010;51(1):95-106). Both literature and internal structural analysis has suggested that this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 5 (Usifo E et al. Ann Hum Genet. 2012;76(5):387-401; Ambry internal data). In addition, alterations affecting the same amino acid (p.C197Y, p.C197F, p.C197G, p.C197R) have also been described in association with FH (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Webb JC et al. J. Lipid Res., 1996 Feb;37:368-81). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.