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

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237918	SCV004022473	likely pathogenic	Hypercholesterolemia, familial, 1	2023-04-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.241C>T (p.Arg81Cys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP4, PP3, PS4_supporting, and PS3_supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00001758 (0.001758%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.817 PP4 - Variant meets PM2 and is identified 1 case with Simon-Broome possible from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PS3_supporting - Level 3 assay: PMID 25647241. HeLa cells, alternative microscopy assay, results - LDL-uptake 68%. PS4_supporting - Variant meets PM2 and is identified in 5 index cases (2 cases with DLCN criteria>=6 from in PMID: 33418990 (Meshkov et al., 2021); at least 1 case with DLCN definite in PMID: 11810272 (Fouchier et al., 2001); 1 case with DLCN definite in PMID: 9712531 (Nissen et al., 1998); 1 case with Simon-Broome possible from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge).
LDLR-LOVD, British Heart Foundation	RCV000237918	SCV000294548	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000237918	SCV000322881	uncertain significance	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 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	pathogenic	Familial hypercholesterolemia	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 81 of the LDLR protein (p.Arg81Cys). This variant is present in population databases (rs730882078, gnomAD 0.002%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9712531, 11810272, 17765246, 21642693, 23375686, 29353225). This variant is also known as p.Arg60Cys. ClinVar contains an entry for this variant (Variation ID: 183083). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 25647241). 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. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000237918	SCV000588490	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000237918	SCV000607434	uncertain significance	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham 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	Hypercholesterolemia, familial, 1	2018-01-10	criteria provided, single submitter	curation
Color Diagnostics, LLC DBA Color Health	RCV001186037	SCV001352367	likely pathogenic	Familial hypercholesterolemia	2023-07-25	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Arg60Cys in the mature protein) replaces arginine with cysteine at codon 81 in the LDLR type A repeat 2 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies using both transfected LDLR-deficient CHO-ldlA7 cells and a high-throughput assay have shown that this variant has an uncertain impact on LDLR activity (PMID: 25647241, 35568682). This variant has been reported in over 15 individuals affected with familial hypercholesterolemia (PMID: 9712531, 10422804, 11810272, 17765246, 20506408, 21642693, 23375686, 28161202, 29353225, 30293936, 33418990, 33454241, 34037665, 36499307) and in an individual affected with premature myocardial infarction (PMID: 30637778). This variant has been identified in 2/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001186037	SCV001422748	uncertain significance	Familial hypercholesterolemia	2020-01-22	criteria provided, single submitter	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).
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.
Revvity Omics, Revvity	RCV000237918	SCV002022666	likely pathogenic	Hypercholesterolemia, familial, 1	2022-04-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000161952	SCV002525314	likely pathogenic	not provided	2022-12-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.R60C; This variant is associated with the following publications: (PMID: 25647241, 21642693, 23375686, 25487149, 9712531, 11810272, 17765246, 20506408, 30971288, 29353225, 28895539, 21382890, 23833242, 10422804, 19318025, 11845603, 33740630, 34037665, 32719484, 31447099, 35339733, 33454241, 36499307, 30637778, 35568682)
New York Genome Center	RCV000237918	SCV002548803	likely pathogenic	Hypercholesterolemia, familial, 1	2021-07-30	criteria provided, single submitter	clinical testing	The inherited c.241C>T (p.Arg81Cys) variant identified in the LDLR gene substitutes a moderately conserved Arginine for Cysteine atamino acid 81/861 (exon 3/18). This variant is also referred to as p.Arg60Cys in some literature. This variant is found with low frequency in gnomAD(v3.1.1)(1heterozygote, 0 homozygotes; allele frequency: 6.57e-6) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.001) and Pathogenic (REVEL; score:0.8169) to the function of the canonical transcripts. This variant is reported as Pathogenic/Likely Pathogenic/Variant of Uncertain Significance in ClinVar (VarID:183083), and has been reported in many affected individuals in the literature [PMID:9712531, 23375686, 20506408, 25647241, others]. Functional studies suggest that the p.Arg81Cys variant may have a mild effect on function,although these studies were performed using overexpression methodology and require additional studies for validation [PMID:25647241]. Given its presence in >10 affected individuals in the literature, low frequency in population databases, and in silico algorithms prediction of a damaging effect, the inherited c.241C>T(p.Arg81Cys) variant identified in the LDLR gene is reported as Likely Pathogenic.
MGZ Medical Genetics Center	RCV000237918	SCV002578965	likely pathogenic	Hypercholesterolemia, familial, 1	2022-04-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002444668	SCV002732853	likely pathogenic	Cardiovascular phenotype	2022-10-11	criteria provided, single submitter	clinical testing	The p.R81C variant (also known as c.241C>T), located in coding exon 3 of the LDLR gene, results from a C to T substitution at nucleotide position 241. The arginine at codon 81, located in LDLR class A repeat 2, is replaced by cysteine, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This particular cysteine alteration has been detected in multiple individuals with familial hypercholesterolemia (FH) from a variety of ethnic backgrounds (Nissen H et al. Clin. Genet., 1998 Jun;53:433-9; Loubser O et al. Clin. Genet., 1999 May;55:340-5; Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Pek SLT et al. Atherosclerosis, 2018 02;269:106-116). This alteration has also been reported in myocardial infarction cohorts, and limited functional studies were inconclusive (Do R et al. Nature, 2015 Feb;518:102-6; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001186037	SCV004046118	likely pathogenic	Familial hypercholesterolemia		criteria provided, single submitter	clinical testing	This variant has been previously reported in individuals with hypercholesterolemia (PMID: 23375686; 33740630; 32719484; 34037665). The c.241C>T (p.Arg81Cys) variant is located in the low-density lipoprotein (LDL) receptor class A repeat domain, which is important for high affinity binding to LDLR ligands (PMID: 3283935). A different change at the same amino acid residue (p.Arg81Ser) has been previously reported in individuals with hypercholesterolemia (PMID: 12124988). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0008% (2/251492). It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the 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	Hypercholesterolemia, familial, 1		no assertion criteria provided	research