ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.542C>G (p.Pro181Arg) (rs557344672)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237262 SCV000503179 likely benign Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / Software predictions: Conflicting
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161959 SCV000189534 not provided not provided no assertion provided in vitro
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000237262 SCV000839992 likely pathogenic Familial hypercholesterolemia 2018-04-25 criteria provided, single submitter clinical testing This c.542C>G (p.Pro181Arg) variant in the LDLR gene has been reported in multiple familial hypercholesterolaemia patients [PMID: 11600564, 11754108, 16250003, 23375686] than that observed as extremely low in general population according to gnomad database. Functional studies showed impairment of precursor LDLR with reduced penetrance associated with this variant [PMID: 21868016]. Multiple in silico predictions suggest this proline to arginine is deleterious. Based upon above evidences, c.542C>G (p.Pro181Arg) variant in the LDLR gene is classified as likely pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000161959 SCV000697237 uncertain significance not provided 2016-03-15 criteria provided, single submitter clinical testing Variant summary: The c.542C>G affects a non-conserved nucleotide, resulting in an amino acid change, Pro to Arg. 3/4 in-silico tools (SNPs&GO not captured here due to low reliability index) predict this variant to be damaging. This variant was found in 7/131378 control chromosomes including the broad and large populations of ExAC at a frequency of 0.0000533, which does not exceed the predicted maximum expected allele frequency for a pathogenic LDLR variant (0.0012508). This variant has been reported in many FH patients/families with both co-segregation of variant with disease as well as lack of co-segregation observed (Garcia-Garcia_ 2001 and Garcia-Garcia _2011). In vitro functional studies showed that variant of interest altered LDLR precursor processing to the mature form, however, the protein activity was normal (Garcia-Garcia _2011) and showed comparable levels of cellular LDL-uptake to wild type (Thormaehlen_2015), suggesting a possible lack of functional effect which needs to be further clarified. Considering all, there is not enough evidence to conclude on either the pathogenicity or neutral effect of this variant. Therefore, this variant has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
LDLR-LOVD, British Heart Foundation RCV000237262 SCV000294785 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237262 SCV000606153 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000237262 SCV000540742 uncertain significance Familial hypercholesterolemia 2016-11-05 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237262 SCV000583701 likely pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

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