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

Total submissions: 16

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).