ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.241C>T (p.Arg81Cys) (rs730882078)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237918 SCV000322881 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research 0/208 non-FH alleles
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237918 SCV000503115 likely pathogenic Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 2 / Functional test / Software predictions: Damaging
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161952 SCV000189527 not provided not provided no assertion provided in vitro
Fundacion Hipercolesterolemia Familiar RCV000237918 SCV000607434 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Iberoamerican FH Network RCV000237918 SCV000748161 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000586143 SCV000697229 pathogenic Early-onset coronary artery disease 2016-09-06 criteria provided, single submitter clinical testing Variant summary: The LDLR c.241C>T (p.Arg81Cys) variant involves the alteration of a conserved nucleotide and results in a replacement of a large size and basic Arginine (R) with a medium size and polar Cysteine (C) located in the ligand binding domain of LDLR. 5/5 in silico tools predict a damaging outcome for this substitution. This variant was found in 1/121500 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0010005). It was observed in several FH patients indicating pathogenicity. In addition, a clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000237918 SCV000544662 likely pathogenic Familial hypercholesterolemia 2016-08-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 81 of the LDLR protein (p.Arg81Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs730882078, ExAC <0.01%). This variant has been reported in several individuals and families affected with familial hypercholesterolemia (PMID: 9712531, 11810272, 17765246, 21642693, 23375686). This variant is also known as p.Arg60Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 183083). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is rare in population databases and has been observed in multiple unrelated individuals with familial hypercholesterolemia. In the absence of conclusive segregation or functional evidence, at this time, this variant has been classified as Likely Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000237918 SCV000294548 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237918 SCV000606046 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000826092 SCV000967594 likely pathogenic Familial hypercholesterolemia - homozygous 2018-02-13 criteria provided, single submitter clinical testing The p.Arg81Cys variant in LDLR (also described as p.Arg81Cys in the literature) has been reported in >18 individuals with familial hypercholesterolemia (FH; Nis sen 1998, Loubser 1999, Fouchier 2001, Bourbon 2008, Alonso 2009, Huijgen 2010, Huijgen 2011, Bertolini 2013), though not all individuals had extremely elevated LDL-cholesterol levels (Huijen 2011). It has been suggested that the p.Arg81Cys variant results in an LDLR protein that does not function as effectively as tha t produced by the wild-type allele, thus resulting in only modest LDL-cholestero l elevations (Huijgen 2010). This variant has also been reported by other clinic al laboratories in ClinVar (Variation ID: 183083) and has been identified in 2/1 11718 European chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org; dbSNP rs730882078). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational pre diction tools and conservation analysis do not provide strong support for or aga inst an impact to the protein. In summary, although additional studies are requi red to fully establish its clinical significance, the p.Arg81Cys variant is like ly pathogenic. ACMG/AMP Criteria applied (Richards 2015): PS4_Strong, PM2.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000237918 SCV000588490 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research

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