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

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000003937	SCV000294789	likely pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000003937	SCV000322902	pathogenic	Familial hypercholesterolemia 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	Familial hypercholesterolemia 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	Familial hypercholesterolemia 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	Familial hypercholesterolemia 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000003937	SCV000588507	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV000587146	SCV000627041	pathogenic	Familial hypercholesterolemia	2019-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with tyrosine at codon 184 of the LDLR protein (p.Cys184Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with familial hypercholesterolemia in several families (PMID: 9678702) and has been observed in multiple unrelated individuals with familial hypercholesterolemia (PMID: 11668627, 20236128, 20828696, 25461735). This variant is also known as p.Cys163Tyr in the literature. ClinVar contains an entry for this variant (Variation ID: 3739). This variant affects a cysteine residue located within an LDLRA domain 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 domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America	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	Familial hypercholesterolemia 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	Familial hypercholesterolemia 1	2018-10-31	criteria provided, single submitter	clinical testing
Color	RCV000587146	SCV000912018	pathogenic	Familial hypercholesterolemia	2018-06-25	criteria provided, single submitter	clinical testing	Pathogenic variant based on current evidence: This variant is a missense variant located in the fourth LDLR type A repeat in the ligand binding domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Although functional assays have not been performed, this variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897) and is expected to have deleterious impact on the LDLR protein folding and stability. This variant has shown strong cosegregation with familial hypercholesterolemia phenotype in several Scottish families (PMID: 9678702). It has also been observed in multiple unrelated individuals affected with familial hypercholesterolemia (PMID: 11668627, 19843101, 20236128, 20828696). This variant is rare in the general population and has been identified in 3/30968 chromosomes (3/15004 non-Finnish European chromosomes) by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare 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	Familial hypercholesterolemia 1	2019-12-30	criteria provided, single submitter	research
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia	RCV000003937	SCV001432613	pathogenic	Familial hypercholesterolemia 1	2019-01-22	criteria provided, single submitter	research
OMIM	RCV000003937	SCV000024102	pathogenic	Familial hypercholesterolemia 1	1998-07-01	no assertion criteria provided	literature only
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000003937	SCV000268570	pathogenic	Familial hypercholesterolemia 1	2008-06-25	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000003937	SCV000606158	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research