Submissions for variant NM_000527.5(LDLR):c.887G>A (p.Cys296Tyr)

dbSNP: rs879254707

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238119	SCV000295029	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000238119	SCV000503249	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 / Software predictions: Conflicting
Iberoamerican FH Network	RCV000238119	SCV000748043	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249084	SCV001423044	uncertain significance	Familial hypercholesterolemia	2020-01-22	criteria provided, single submitter	curation	The p.Cys296Tyr variant in LDLR has been reported in 3 individuals with familial hypercholesterolemia (PMID: 23375686, 21722902, 20809525), and was absent from large population studies. This variant has also been reported in ClinVar as likely pathogenic (Variation ID: rs879254707). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS4_supporting (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001249084	SCV001584409	pathogenic	Familial hypercholesterolemia	2023-06-27	criteria provided, single submitter	clinical testing	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.Cys296 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 23375686), 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). 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: 251502). This missense change has been observed in individuals with autosomal dominant and autosomal recessive familial hypercholesterolemia (PMID: 20809525, 21722902, 23375686, 24014831). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 296 of the LDLR protein (p.Cys296Tyr).
Ambry Genetics	RCV002374399	SCV002685505	likely pathogenic	Cardiovascular phenotype	2018-01-15	criteria provided, single submitter	clinical testing	The p.C296Y variant (also known as c.887G>A), located in coding exon 6 of the LDLR gene, results from a G to A substitution at nucleotide position 887. The cysteine at codon 296 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in individuals with familial hypercholeterolemia (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). 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 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). Futhermore, an alteration affecting this amino acid (p.C296S) has been reported in association with FH (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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238119	SCV000606258	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research