Submissions for variant NM_000527.5(LDLR):c.647G>A (p.Cys216Tyr)

dbSNP: rs879254611

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237153	SCV000294845	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	RCV000237153	SCV000503195	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 , family member = 6 / Software predictions: Damaging
Fundacion Hipercolesterolemia Familiar	RCV000237153	SCV000607479	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791421	SCV000752406	pathogenic	Familial hypercholesterolemia	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 216 of the LDLR protein (p.Cys216Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypercholesterolemia (PMID: 14974088, 33732287; Invitae). ClinVar contains an entry for this variant (Variation ID: 251346). 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 with a positive predictive value of 95%. 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). This variant disrupts the p.Cys216 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 15241806, 18096825), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002356334	SCV002654815	likely pathogenic	Cardiovascular phenotype	2018-10-15	criteria provided, single submitter	clinical testing	The p.C216Y variant (also known as c.647G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 647. The cysteine at codon 216, located in LDLR class A repeat 5, is replaced by tyrosine, 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 cysteine alteration has been detected in a proband with hypercholesterolemia, and in the proband's reportedly affected child (Dedoussis GV et al. Hum Mutat. 2004;23:285-6). 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 affecting this codon (p.C216R, c.646T>C) has also been reported in an FH cohort (Mozas P et al. Hum Mutat. 2004;24:187). 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.
Rajaie Cardiovascular, Medical and Research Center, Iran University of Medical Sciences	RCV000237153	SCV001467723	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research