ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.551G>A (p.Cys184Tyr) (rs121908039)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000003937 SCV000294789 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000003937 SCV000322902 pathogenic Familial hypercholesterolemia 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 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 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 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000003937 SCV000588507 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Invitae RCV000587146 SCV000627041 pathogenic Familial hypercholesterolemias 2018-11-12 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 hypercholesterolemias 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 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 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000587146 SCV000912018 pathogenic Familial hypercholesterolemias 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 Familial hypercholesterolemia - homozygous 2018-02-13 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) a nd segregated with disease in at least 11 affected relatives from 4 families (Le e 1998, Graham 1999, Fouchier 2001, Wang 2001, Bourbon 2008, Jannes 2015, Martin 2016). It has also been reported by other clinical laboratories in ClinVar (Var iation ID 3739). This variant has been identified in 3/15004 European chromosome s by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs121908039). This frequency is low enough to be consistent with the freq uency of FH in the general population. Computational prediction tools and conser vation 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 computati onal evidence. ACMG/AMP Criteria applied (Richards 2015): PS4, PP1_Strong, PM2, PP3.
OMIM RCV000003937 SCV000024102 pathogenic Familial hypercholesterolemia 1998-07-01 no assertion criteria provided literature only
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000003937 SCV000268570 pathogenic Familial hypercholesterolemia 2008-06-25 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000003937 SCV000606158 pathogenic Familial hypercholesterolemia no assertion criteria provided research

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