Submissions for variant NM_000527.5(LDLR):c.888C>G (p.Cys296Trp)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002375991	SCV002685333	likely pathogenic	Cardiovascular phenotype	2018-01-15	criteria provided, single submitter	clinical testing	The p.C296W variant (also known as c.888C>G), located in coding exon 6 of the LDLR gene, results from a C to G substitution at nucleotide position 888. The cysteine at codon 296 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). In addition, internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 7 (Rudenko G et al. Science. 2002 Dec;298(5602):2353-8). Furthermore, other alterations affecting this amino acid (p.C296Y and p.C296S) have been reported in association with FH (Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Vaca G et al. Atherosclerosis, 2011 Oct;218:391-6; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003100047	SCV003443156	likely pathogenic	Familial hypercholesterolemia	2023-04-24	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (Invitae). 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.Cys296 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20809525, 21722902, 23375686). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 1764981). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 296 of the LDLR protein (p.Cys296Trp).