ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1897C>T (p.Arg633Cys) (rs746118995)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211568 SCV000268648 pathogenic Familial hypercholesterolemia 2015-01-09 no assertion criteria provided clinical testing
Color RCV000590441 SCV000909183 likely pathogenic Familial hypercholesterolemias 2018-06-19 criteria provided, single submitter clinical testing Likely Pathogenic variant based on current evidence: This variant (also known as p.Arg612Cys in the mature protein) is a missense variant located in the sixth LDLR type B repeat of the EGF precursor homology 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. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in the literature in 10+ unrelated British, Canadian, Italian, Chinese, Spanish and Czech individuals diagnosed with familial hypercholesterolemia (PMID: 9259195, 9452078, 19446849, 19538517, 19843101, 21376320, 23375686, 27765764, 28028493, 28235710). This variant is rare in the general population and has been identified in 3/246268 chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence this variant is classified as Likely Pathogenic.
Fundacion Hipercolesterolemia Familiar RCV000211568 SCV000607653 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
GeneDx RCV000486101 SCV000567421 pathogenic not provided 2018-10-25 criteria provided, single submitter clinical testing The R633C variant in the LDLR gene has been reported previously, denoted as R612C due to alternative nomenclature, in multiple individuals with familial hypercholesterolemia (Day et al., 1997; Tosi et al., 2007; Chiou and Charng, 2010; Bertolini et al., 2013). The R633C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R633C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret R633C as a pathogenic variant.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000211568 SCV000839998 likely pathogenic Familial hypercholesterolemia 2018-01-14 criteria provided, single submitter clinical testing The c.1897C>T (p.Arg633Cys) variant in the LDLR gene has been reported in several unrelated individuals with familial hypercholesterolemia (PMID: 9259195, 15241806, 19446849, 19843101, 21376320, 22698793, 23375686). Moreover, two other variants at the same residue (p.Arg633His, and p.Arg633Leu) have also been described in multiple individuals with familial hypercholesterolemia (PMID: 16250003, 22390909) suggesting that the Arg633 residue is critical for normal functioning of the LDLR protein. In light of the currently available data this variant in the LDLR gene is classified likely pathogenic
Illumina Clinical Services Laboratory,Illumina RCV000211568 SCV000914827 pathogenic Familial hypercholesterolemia 2017-04-28 criteria provided, single submitter clinical testing The LDLR c.1897C>T (p.Arg633Cys) variant has been reported in at least eight studies and is found in a total of at least 11 individuals with familial hypercholesterolemia, including one who carried the variant in a compound heterozygous state along with a deletion and in a heterozygous state in ten individuals (Day et al. 1997; Mozas et al. 2004; Taylor et al. 2007; Guardamagna et al. 2009; Taylor et al. 2009; Chiou et al. 2010; Tichý et al. 2012; Bertolini et al. 2013). The p.Arg633Cys variant was absent from 100 controls, and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium, in a region of good sequence coverage, and hence is presumed to be rare. Based on the evidence, the p.Arg633Cys variant is classified as pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000590441 SCV000697214 pathogenic Familial hypercholesterolemias 2016-11-08 criteria provided, single submitter clinical testing Variant summary: The LDLR c.1897C>T (p.Arg633Cys) variant, alternatively also known as R612C, is located in EGF precursor homology domain of the LDLR protein (Mozas_2004, Bertolini_2013) and 4/4 in silico tools predict a damaging outcome for this substitution. This variant is absent in 121614 control chromosomes including broad and large populations from ExAC. In literature, this variant is widely reported as a pathogenic variant and is found in several FH patients. Other missense variants in this codon, p.Arg633Leu and p.Arg633His, have been reported as FH patients and are classified as pathogenic/likely pathogenic in ClinVar, suggesting that the codon p.Arg633 is mutational hot-spot. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000590441 SCV000544682 pathogenic Familial hypercholesterolemias 2018-09-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 633 of the LDLR protein (p.Arg633Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (rs746118995, ExAC no frequency). This variant has been reported in multiple unrelated individuals affected with familial hypercholesterolemia (PMID: 9259195, 15241806, 19446849, 19843101, 21376320, 22698793, 23375686), including one case of homozygous familial hypercholesterolemia (PMID: 19538517). This variant is also known as p.Arg612Cys in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is absent from population databases, is predicted to be deleterious, and has been observed in many individuals with familial hypercholesterolemia. For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000211568 SCV000295745 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211568 SCV000606552 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000826210 SCV000967775 likely pathogenic Familial hypercholesterolemia - homozygous 2019-03-04 criteria provided, single submitter clinical testing The p.Arg633Cys variant in LDLR has been reported in at least 11 individuals wit h familial hypercholesterolemia (FH), including one homozygote (Day 1997, Mozas 2004, Guardamagna 2009, Taylor 2009, Chiou 2011, Tichy 2012, Bertolini 2013, Xia ng 2017, Medieros 2017). This variant has been reported in ClinVar (Variation ID : 226379) and has also been identified in 1/30782 South Asian chromosomes by th e Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Comput ational prediction tools and conservation analysis suggest that the p.Arg833Cys variant may impact the protein. Two other variants at this amino acid position h ave been reported in at least 4 individuals with FH (p.Arg633Leu and p.Arg633His ). In summary, although additional studies are required to fully establish its c linical significance, the p.Arg633Cys variant is likely pathogenic. ACMG/AMP Cr iteria applied: PS4_Moderate, PM2, PM5_Supporting, PP3.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000211568 SCV000588622 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000211568 SCV000540848 likely pathogenic Familial hypercholesterolemia 2016-11-05 criteria provided, single submitter clinical testing
Robarts Research Institute,Western University RCV000211568 SCV000484757 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211568 SCV000583906 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

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