Total submissions: 15
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000237262 | SCV000294785 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Centre de Génétique Moléculaire et Chromosomique, |
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, |
RCV000237262 | SCV000540742 | uncertain significance | Hypercholesterolemia, familial, 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | |
U4M - |
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, |
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. |
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. |
Color Diagnostics, |
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, |
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, the in silico prediction for this alteration is inconclusive. 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. |
Dept. |
RCV000161959 | SCV000189534 | not provided | not provided | no assertion provided | in vitro | ||
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000237262 | SCV000606153 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research | ||
Natera, |
RCV001181335 | SCV001456144 | uncertain significance | Familial hypercholesterolemia | 2020-09-16 | no assertion criteria provided | clinical testing | |
Zotz- |
RCV000237262 | SCV004041648 | uncertain significance | Hypercholesterolemia, familial, 1 | 2023-10-09 | no assertion criteria provided | clinical testing |