ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.542C>G (p.Pro181Arg)

dbSNP: rs557344672
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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 RCV000237262 SCV000294785 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
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 Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / Software predictions: Conflicting
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation RCV000237262 SCV000540742 uncertain significance Hypercholesterolemia, familial, 1 2016-11-05 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237262 SCV000583701 likely pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004525832 SCV000697237 uncertain significance not specified 2024-03-01 criteria provided, single submitter clinical testing Variant summary: LDLR c.542C>G (p.Pro181Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.7e-05 in 261608 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.542C>G has been reported in many FH patients/families with both co-segregation of variant with disease as well as lack of co-segregation observed (example, 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. The following publications have been ascertained in the context of this evaluation (PMID: 23375686, 16627557, 34297352, 25487149, 21310417, 18279815, 16250003, 21868016, 11668640, 11754108, 14508510, 20045108, 35913489, 25647241, 22698793, 31447099). ClinVar contains an entry for this variant (Variation ID: 183089). Based on the evidence outlined above, the variant was classified as uncertain significance.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000237262 SCV000839992 likely pathogenic Hypercholesterolemia, familial, 1 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.
Color Diagnostics, LLC DBA Color Health RCV001181335 SCV001346460 likely pathogenic Familial hypercholesterolemia 2023-08-10 criteria provided, single submitter clinical testing This missense variant replaces proline with arginine at codon 181 of the LDLR protein. This variant is also known as p.Pro160Arg in the mature protein. This variant alters a conserved proline residue in the LDLR type A repeat 4 ligand binding domain of the LDLR protein (a.a. 146-186), where pathogenic missense variants are found enriched (ClinVar-LDLR). 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). Functional studies have shown that the variant interfered with LDLR precursor processing to the mature form, although the mature mutant protein exhibited wild-type like LDLR activity (PMID: 21868016, 25647241). This variant has been reported in at least ten individuals affected with familial hypercholesterolemia (PMID: 11668640, 11754108, 20045108, 21310417, 21868016, 22698793, 23375686, 32977124; ClinVar SCV000503179.1, SCV000583701.1, SCV000540742.1). It has also been reported in three individuals affected with early-onset myocardial infarction (PMID: 25647241). This variant has been identified in 6/251308 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000161959 SCV001469531 uncertain significance not provided 2020-07-24 criteria provided, single submitter clinical testing
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II RCV000237262 SCV001653596 likely pathogenic Hypercholesterolemia, familial, 1 2021-05-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV002345556 SCV002652911 uncertain significance Cardiovascular phenotype 2018-11-15 criteria provided, single submitter clinical testing The p.P181R variant (also known as c.542C>G), located in coding exon 4 of the LDLR gene, results from a C to G substitution at nucleotide position 542. The proline at codon 181 is replaced by arginine, an amino acid with dissimilar properties. This variant (also described as p.P160R) has been reported in multiple individuals with familial hypercholesterolemia (FH) from a variety of ethnic backgrounds (Chaves FJ et al. J. Clin. Endocrinol. Metab., 2001 Oct;86:4926-32; Kuhrová V et al. Hum. Mutat., 2002 Jan;19:80; Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6). In one family with FH, this variant was reported in an asymptomatic proband, as well as in her affected mother and her affected maternal aunt, but was not detected in a second affected maternal aunt (Garcia-Garcia AB et al. Atherosclerosis, 2011 Oct;218:423-30). This variant was also detected in three early onset myocardial infarction (MI) cases and in one non-MI control, but only one of these individuals was reported to have elevated LDL-C levels (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). One functional study suggested this variant affects LDLR processing; however, LDLR activity did not appear to be impacted, and additional in vitro studies showed no significant change in LDL uptake (Garcia-Garcia AB et al. Atherosclerosis, 2011 Oct;218:423-30; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001181335 SCV003444822 pathogenic Familial hypercholesterolemia 2023-12-07 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 181 of the LDLR protein (p.Pro181Arg). This variant is present in population databases (rs557344672, gnomAD 0.005%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 11754108, 16250003, 20045108, 21868016, 22698793; Invitae). This variant is also known as P160R. ClinVar contains an entry for this variant (Variation ID: 183089). 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 does not substantially affect LDLR function (PMID: 21868016, 25647241). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV000237262 SCV004812136 pathogenic Hypercholesterolemia, familial, 1 2024-03-25 criteria provided, single submitter clinical testing Criteria applied: PS4_MOD,PM1,PM2_SUP_MOD,PM5,PP3,PP4
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161959 SCV000189534 not provided not provided no assertion provided in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237262 SCV000606153 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research
Natera, Inc. RCV001181335 SCV001456144 uncertain significance Familial hypercholesterolemia 2020-09-16 no assertion criteria provided clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas RCV000237262 SCV004041648 uncertain significance Hypercholesterolemia, familial, 1 2023-10-09 no assertion criteria provided clinical testing

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