Total submissions: 21
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
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). |
| Institute of Human Genetics, |
RCV000237262 | SCV005871378 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2024-12-09 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV000237262 | SCV005426453 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2024-09-26 | 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. |
| Mayo Clinic Laboratories, |
RCV000161959 | SCV005413305 | likely pathogenic | not provided | 2024-06-03 | criteria provided, single submitter | clinical testing | PM1, PM2, PM3, PM5_supporting, PS3_supporting, PS4_moderate |
| Gene |
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) |
| Institute of Human Genetics, |
RCV000237262 | SCV004812136 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2024-09-10 | criteria provided, single submitter | clinical testing | Criteria applied: PS4_MOD,PM1,PM2,PM5,PP3 |
| Labcorp Genetics |
RCV001181335 | SCV003444822 | pathogenic | Familial hypercholesterolemia | 2024-11-03 | 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; internal data). This variant is also known as P160R. ClinVar contains an entry for this variant (Variation ID: 183089). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. |
| Ambry Genetics | RCV002345556 | SCV002652911 | likely pathogenic | Cardiovascular phenotype | 2024-11-18 | 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) was reported in multiple individuals with features consistent with familial hypercholesterolemia (FH) (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; Garcia-Garcia AB et al. Atherosclerosis, 2011 Oct;218:423-30 Tichý L et al. Atherosclerosis. 2012 Aug;223(2):401-8; Thormaehlen AS et al. PLoS Genet, 2015 Feb;11:e1004855; Di Taranto MD et al. Clin Genet, 2021 Nov;100:529-541; Ambry internal data). In one family, this variant was detected in affected individuals; however, an affected individual did not have this variant (Garcia-Garcia AB et al. Atherosclerosis, 2011 Oct;218:423-30). One functional study suggested this variant affects LDLR processing; however, LDLR activity and LDL uptake did not appear impacted (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. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Laboratory of molecular diagnosis of dyslipidemias, |
RCV000237262 | SCV001653596 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2021-05-24 | criteria provided, single submitter | clinical testing | |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000161959 | SCV001469531 | uncertain significance | not provided | 2020-07-24 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV001181335 | SCV001346460 | likely pathogenic | Familial hypercholesterolemia | 2024-12-23 | 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. 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. |
| Human Genome Sequencing Center Clinical Lab, |
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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
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. |
| U4M - |
RCV000237262 | SCV000583701 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
| Molecular Genetics Laboratory, |
RCV000237262 | SCV000540742 | uncertain significance | Hypercholesterolemia, familial, 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | |
| LDLR- |
RCV000237262 | SCV000294785 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Zotz- |
RCV000237262 | SCV004041648 | uncertain significance | Hypercholesterolemia, familial, 1 | 2023-10-09 | no assertion criteria provided | clinical testing | |
| Natera, |
RCV001181335 | SCV001456144 | uncertain significance | Familial hypercholesterolemia | 2020-09-16 | no assertion criteria provided | clinical testing | |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000237262 | SCV000606153 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research | ||
| Centre de Génétique Moléculaire et Chromosomique, |
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 |
| Dept. |
RCV000161959 | SCV000189534 | not provided | not provided | no assertion provided | in vitro |