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

dbSNP: rs557344672

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237262	SCV005328534	likely pathogenic	Hypercholesterolemia, familial, 1	2024-02-23	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.542C>G (p.Pro181Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PS3_Moderate, PS4_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.00005 (0.005%) in European (Non-Finnish) exomes+genomes (gnomAD v4.0.0). PM1: Variant meets PM2 and is a missense in exon 4. PS3_Moderate: Level 2 assay: PMID 21868016 (Garcia-Garcia A et al., 2011): COS-7 cells. Mature/precursor LDLR forms ratio ~60% ---- Overall LDLR biosynthesis is below 70% of wild-type activity. PS4_Moderate, PP4: Variant meets PM2 and is identified in at least 6 unrelated index cases who fulfill criteria for FH (1 case from PMID 16250003 (Fouchier SW et al., 2005); 2 cases with MedPed and Simon Broome criteria from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic, and PMID 22698793 (Tichý L et al., 2012); 2 cases meeting Simon Broome and DLCN criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 1 case with DLCN score>=6 from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia).
LDLR-LOVD, British Heart Foundation	RCV000237262	SCV000294785	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
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.
Labcorp Genetics (formerly Invitae), Labcorp	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	likely pathogenic	Hypercholesterolemia, familial, 1	2024-09-10	criteria provided, single submitter	clinical testing	Criteria applied: PS4_MOD,PM1,PM2,PM5,PP3
GeneDx	RCV000161959	SCV005078058	uncertain significance	not provided	2024-05-24	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; Functional studies demonstrated that p.(P181R) is associated with altered LDLR precursor processing; however, it does not result in altered receptor activity (PMID: 21868016); Also known as p.(P160R); This variant is associated with the following publications: (PMID: 16250003, 21310417, 14508510, 20045108, 23375686, 11524740, 25487149, 22698793, 11754108, 11600564, 18279815, 25647241, 21868016, 31447099, 37409534, 35913489, 32977124)
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161959	SCV000189534	not provided	not provided		no assertion provided	in vitro
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	flagged submission	clinical testing	subject mutated among 2600 FH index cases screened = 1 / Software predictions: Conflicting
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