Submissions for variant NM_000527.5(LDLR):c.551G>A (p.Cys184Tyr)

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000003937	SCV002506389	pathogenic	Hypercholesterolemia, familial, 1	2022-04-22	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.551G>A (p.Cys184Tyr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PM1, PS3, PS4, PP1_Strong, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00019 (0.019%) in European Non-Finnish genomes (gnomAD v2.1.1). PP3 - REVEL = 0.85, which is above the threshold of 0.75. PM1 - variant meets PM2 and is located in exon 4. PS3 - Level 1 functional studies performed - Heterologous cells (CHO), FACS: Result of normal cell surface LDLR (100%), 4% LDL binding and 18% LDL uptake, compared to wild-type (PMID: 34167030). PS4 - Variant meets PM2 and is identified in at least 22 unrelated index cases who fulfill clinical criteria for FH (8 cases with SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge; 6 cases with DLCN criteria from Robarts Research Institute; 5 cases with DLCN criteria from PathWest Laboratory Medicine WA; 2 cases with DLCN criteria from Color; 1 case with MEDPED criteria from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory). PP1_Strong - Variant segregates with phenotype in 14 informative meioses from 8 families (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – 4 families: 8 relatives affected with the variant and 1 relative unaffected without the variant; Robarts Research Institute – 2 families: 2 relatives affected with the variant; PathWest Laboratory Medicine WA – 2 families: 2 affected relative with the variant and 1 unaffected relative without the variant) PP4 - variant meets PM2 and is identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded.
LDLR-LOVD, British Heart Foundation	RCV000003937	SCV000294789	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000003937	SCV000322902	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/190 non-FH alleles; 0/100 healthy control individuals
Robarts Research Institute, Western University	RCV000003937	SCV000484697	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000003937	SCV000503181	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 2 /FH-Rome-2 / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000003937	SCV000583702	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000003937	SCV000588507	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV000587146	SCV000627041	pathogenic	Familial hypercholesterolemia	2023-12-13	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 184 of the LDLR protein (p.Cys184Tyr). This variant is present in population databases (rs121908039, gnomAD 0.02%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9678702, 11668627, 20236128, 20828696, 25461735). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys163Tyr. ClinVar contains an entry for this variant (Variation ID: 3739). 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). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587146	SCV000697238	pathogenic	Familial hypercholesterolemia	2016-07-05	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.551G>A (p.Cys184Tyr) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. Cys184 is located in repeat 4 of the LDLR class A (cyteine-rich) repeat, and Cys184 is highly conserved across species. In LDL receptors, the class A domains form the binding site for LDL and calcium, and numerous familial hypercholestorolemia pathogenic LDLR variants alter the calcium coordinating residue of LDL-A domains.This variant was absent in 121144 control chromosomes, but has been cited in many FH families in the literature and has been shown to co-segregate with disease in multiple independent families (Lee_JMG_1998). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is a commonly known FH-causing LDLR variant and was classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000003937	SCV000840000	likely pathogenic	Hypercholesterolemia, familial, 1	2018-02-20	criteria provided, single submitter	clinical testing	This c.551G>A (p.Cys184Tyr) variant in the LDLR gene has been reported to segregate with familial hypercholesterolemia in several families (PMID: 9678702) and has been reported in multiple unrelated patients with familial hypercholesterolemia (PMID: 10559517, 11668627, 17765246, 20236128) and is rarely detected in the general population. Cysteine residue at position 184 of the LDLR protein is highly evolutionarily conserved. Based on this information, the c.551G>A (p.Cys184Tyr) variant in the LDLR gene is classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000003937	SCV000894168	pathogenic	Hypercholesterolemia, familial, 1	2021-10-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000587146	SCV000912018	pathogenic	Familial hypercholesterolemia	2023-04-12	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 184 in the fourth LDLR type A repeat in the ligand binding domain of the LDLR protein. This variant is also known as p.Cys163Tyr in the mature protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes a significant reduction in LDL binding and uptake (PMID: 34167030). This variant has been reported in over 20 individuals affected with familial hypercholesterolemia (PMID: 11668627, 19843101, 20236128, 20828696, 31345425, 32331935, 34037665, 34297352; Color internal data). It has been shown that this variant segregates with disease in over 10 affected individuals across 3 families (PMID: 9678702). This variant has been identified in 3/31402 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Cys184Arg, is reported to be disease-causing (ClinVar variation ID: 251294), indicating that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000826197	SCV000967747	pathogenic	Homozygous familial hypercholesterolemia	2019-03-03	criteria provided, single submitter	clinical testing	The p.Cys184Tyr variant in LDLR (also described as p.Cys163Tyr in the literature) has been reported in >15 individuals with familial hypercholesterolemia (FH) and segregated with disease in at least 11 affected relatives from 4 families (Lee 1998, Graham 1999, Fouchier 2001, Wang 2001, Bourbon 2008, Jannes 2015, Martin 2016). It has also been reported by other clinical laboratories in ClinVar (Variation ID 3739). This variant has been identified in 3/15004 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs121908039). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analysis suggest that the p.Cys184Tyr variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon presence in multiple affected individuals, segregation studies, very low frequency in the general population and computational evidence. The ACMG/AMP Criteria applied (Richards 2015): PS4, PP1_Strong, PM2, PP3.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000003937	SCV001192818	pathogenic	Hypercholesterolemia, familial, 1	2019-12-30	criteria provided, single submitter	research
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000003937	SCV001432613	pathogenic	Hypercholesterolemia, familial, 1	2019-01-22	criteria provided, single submitter	research
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000003937	SCV001653597	likely pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001535532	SCV002046959	likely pathogenic	not provided	2020-10-17	criteria provided, single submitter	clinical testing	The variant has been reported in multiple families affected with familial hypercholesterolemia in the published literature (PMID: 24627126 (2014), 25461735 (2015), 27680772 (2016), 27765764 (2016), 31345425 (2019), 32331935 (2020)) as well as in individuals with early-onset myocardial infarction (PMID: 30586733 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is disease causing and damaging. A different variant affecting the same amino acid position has been described as pathogenic. Based on the available information, the variant is predicted to be likely pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001535532	SCV002049430	pathogenic	not provided	2021-11-19	criteria provided, single submitter	clinical testing	The LDLR c.551G>A; p.Cys184Tyr variant (rs121908039) is reported in the literature in 15 individuals affected with high LDL-C (Sturm 2021). Moreover, this variant has been identified as a recurrent co-segregating allele within three familial hypercholesterolemia families with ten informative meiosis cases (Lee 1998). This variant is also reported in ClinVar (Variation ID: 3739). This variant is found in the general population with an overall allele frequency of 0.0096% (3/31402 alleles) in the Genome Aggregation Database. The cysteine at codon 184 is highly conserved, is involved in disulfide bond formation of LDLR, and computational analyses predict that this variant is deleterious (REVEL: 0.854). Based on available information, this variant is considered to be pathogenic
Ambry Genetics	RCV002345227	SCV002653572	pathogenic	Cardiovascular phenotype	2022-03-07	criteria provided, single submitter	clinical testing	The p.C184Y pathogenic mutation (also known as c.551G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 551. The cysteine at codon 184 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the ligand binding domain. This variant has been described in numerous familial hypercholesterolemia (FH) cohorts (Hobbs HH et al. Hum. Mutat. 1992;1(6):445-66; Graham CA et al. Atherosclerosis. 1999;147(2):309-16; Hooper AJ et al. Atherosclerosis. 2012;224(2):430-4; Taylor A et al. Clin Genet. 2010; 77(6):572-80; Wang J et al. Arterioscler. Thromb. Vasc. Biol. 2016;36:2439-2445). In one study, this variant was observed to co-segregate with FH in multiple relatives from three families (Lee WK et al. J Med Genet. 1998;35(7):573-8). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 4 (Ambry internal data). Another alteration at the same codon, p.C184R (c.550T>C), has also been described in patients with FH (Pimstone SN et al. Arterioscler Thromb Vasc Biol. 1998;18(2):309-15). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity	RCV000003937	SCV003827673	pathogenic	Hypercholesterolemia, familial, 1	2022-10-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001535532	SCV004169114	pathogenic	not provided	2023-11-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies show that LDL-deficient CHO-ldlA7 cells transfected with the p.(C184Y)-LDL demonstrates impaired binding activity (PMID: 34167030); Also reported as FH Rome-2 and p.(C163Y) due to alternate nomenclature; This variant is associated with the following publications: (PMID: 31447099, 30586733, 9678702, 10559517, 11668627, 11810272, 20236128, 20828696, 25461735, 28873201, 33303402, 32719484, 32331935, 33740630, 33418990, 34037665, 27765764, 34363016, 22883975, 1301956, 32041611, 27680772, 31345425, 34297352, 24627126, 30583242, 34906454, 34167030)
OMIM	RCV000003937	SCV000024102	pathogenic	Hypercholesterolemia, familial, 1	1998-07-01	no assertion criteria provided	literature only
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000003937	SCV000268570	pathogenic	Hypercholesterolemia, familial, 1	2008-06-25	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000003937	SCV000606158	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000587146	SCV001456145	pathogenic	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001535532	SCV001749502	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 11-12-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.