ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.241C>T (p.Arg81Cys)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237918 SCV000294548 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237918 SCV000322881 uncertain significance Familial hypercholesterolemia 1 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 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 2 / Functional test / Software predictions: Damaging
Invitae RCV001186037 SCV000544662 likely pathogenic Familial hypercholesterolemia 2020-08-25 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 0.001%). This variant has been reported in several individuals and families affected with familial hypercholesterolemia (PMID: 9712531, 11810272, 17765246, 21642693, 23375686, 29353225). 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Arg81 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 21382890), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000237918 SCV000588490 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000237918 SCV000607434 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Iberoamerican FH Network RCV000237918 SCV000748161 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826092 SCV000967594 likely pathogenic Homozygous familial hypercholesterolemia 2021-03-22 criteria provided, single submitter clinical testing The p.Arg81Cys variant in LDLR (also described as p.Arg60Cys in the literature) has been reported in >18 individuals with familial hypercholesterolemia (FH; Nissen 1998 PMID: 9712531, Loubser 1999 PMID: 10422804, Fouchier 2001 PMID: 11810272, Bourbon 2008 PMID: 17765246, Alonso 2009 PMID: 19318025, Huijgen 2010 PMID: 20506408, Huijgen 2011 PMID: 21642693, Bertolini 2013 PMID: 23375686), though not all individuals had extremely elevated LDL-cholesterol levels (Huijgen 2011 PMID: 21642693). It has been suggested that the p.Arg81Cys variant results in an LDLR protein that does not function as effectively as that produced by the wild-type allele, thus resulting in only modest LDL-cholesterol elevations (Huijgen 2010 PMID: 20506408). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 183083) and has been identified in 0.02% (2/113766) European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. In vitro functional studies suggest that this variant does not have a clear impact on LDL uptake into cells (Thormaehlen 2015 PMID: 25647241). Computational prediction tools and conservation analysis are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg81Cys variant is likely pathogenic. ACMG/AMP Criteria applied: PS4_Strong, PM2_supporting, PP3.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000237918 SCV001132526 likely pathogenic Familial hypercholesterolemia 1 2018-01-10 criteria provided, single submitter curation
Color Health, Inc RCV001186037 SCV001352367 likely pathogenic Familial hypercholesterolemia 2019-12-16 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000161952 SCV001433516 likely pathogenic not provided 2019-12-16 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001186037 SCV001434983 likely pathogenic Familial hypercholesterolemia 2019-08-20 criteria provided, single submitter clinical testing The c.241C>T (p.Arg81Cys) variant in the LDLR gene has been reported in multiple unrelated individuals and families with familial hypercholesterolemia (PMID: 9712531, 10422804, 11810272, 17765246, 19318025, 21642693, 23375686, 25487149) and is rare in population databases. Multiple lines of in silico algorithms have predicted this Arg81Cys change to be deleterious. Therefore, this c.241C>T (p.Arg81Cys) variant is classified as likely pathogenic.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161952 SCV000189527 not provided not provided no assertion provided in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237918 SCV000606046 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Broad Institute Rare Disease Group, Broad Institute RCV001186037 SCV001422748 uncertain significance Familial hypercholesterolemia 2020-01-22 no assertion criteria provided curation The p.Arg81Cys variant in LDLR has been reported in at least 12 individuals (2 African, 1 Italian, 1 Malaysian, 1 Venezuelan, 6 Dutch, 1 Portuguese) with familial hypercholesterolemia (PMID: 11845603, 28161202, 29353225, 28895539, 10422804, 21642693, 9712531, 17765246, 11810272), and has been identified in 0.002% (2/113766) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs730882078). This variant has (also) been reported in ClinVar as having conflicting interpretations of pathogenicity (Variation ID: 183083). In vitro functional studies provide some evidence that the p.Arg81Cys variant may slightly impact protein function (PMID: 25647241). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_moderate, PP3, PS3_supporting (Richards 2015).

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