Submissions for variant NM_000527.5(LDLR):c.2483A>G (p.Tyr828Cys)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000003893	SCV000296023	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000003893	SCV000588670	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
GeneDx	RCV000162025	SCV002520116	pathogenic	not provided	2022-05-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect through defective uptake, internalization, and degradation (Davis et al., 1986; Ranheim et al., 2006; Thormaehlen et al., 2015); Also denoted as Y807C and FH J.D-Bari due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 23375686, 28126585, 23733886, 189940, 8882879, 19446849, 200368, 31387896, 20145306, 25461735, 3955657, 23105264, 32041611, 33740630, 32719484, 33508743, Thajer2022, 25647241, 16740646)
Ambry Genetics	RCV002426485	SCV002740428	pathogenic	Cardiovascular phenotype	2024-01-05	criteria provided, single submitter	clinical testing	The p.Y828C pathogenic mutation (also known as c.2483A>G), located in coding exon 17 of the LDLR gene, results from an A to G substitution at nucleotide position 2483. The tyrosine at codon 828 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been described in several patients with familial hypercholesterolemia (FH) (Brown MS et al. Cell, 1976 Dec;9:663-74; Goldstein JL et al. Cell, 1977 Nov;12:629-41; Reshef A et al. Hum Genet. 1996;98:581-6; Chmara M et al. J Appl Genet. 2010;51:95-106; Bertolini S et al. Atherosclerosis. 2013;227:342-8). In functional in vitro analyses, this variant has demonstrated decreased ability to bind and internalize low-density lipoprotein (LDL), thus inhibiting endocytosis (Davis CG et al. Cell. 1986;45:15-24). Internal structural analysis suggests that this variant, which impacts the NPXY motif required for receptor internalization, will disrupt protein function (Chen WJ et al. J Biol Chem. 1990;265(6):3116-23; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002512729	SCV003443111	pathogenic	Familial hypercholesterolemia	2022-12-23	criteria provided, single submitter	clinical testing	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. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LDLR function (PMID: 3955657, 16740646). ClinVar contains an entry for this variant (Variation ID: 3704). This variant is also known as p.Tyr807Cys, or JD Bari. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 23375686, 25461735, 28126585, 31387896). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 828 of the LDLR protein (p.Tyr828Cys).
Revvity Omics, Revvity	RCV000003893	SCV003825411	pathogenic	Hypercholesterolemia, familial, 1	2022-07-29	criteria provided, single submitter	clinical testing
OMIM	RCV000003893	SCV000024058	pathogenic	Hypercholesterolemia, familial, 1	1986-04-11	no assertion criteria provided	literature only
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000162025	SCV000189628	not provided	not provided		no assertion provided	in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000003893	SCV000606662	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research