Total submissions: 15
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000238570 | SCV004022435 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2023-04-28 | reviewed by expert panel | curation | The NM_000527.5(LDLR):c.846C>A (p.Phe282Leu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3_Supporting, PS4_Supporting, PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3_Supporting: Level 3 assays: PMID 25647241: HeLa cells, In vitro microscopy assays - result - 66% wild type LDLR expression (below 70%, Figure 3). ---- functional study is consistent with damaging effect. So, PS3_Supporting is met. PS4_Supporting: Variants meets PM2 and is identified in 2 cases from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille with diagnosis of probable FH based on DLCN criteria. So, PS4_Supporting is met. PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes (gnomAD v2.1.1). So, PM2 is met. PP3: REVEL=0.877. It is above 0.75, so PP3 is met. PP4: Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details), after alternative causes for high cholesterol were excluded. |
LDLR- |
RCV000238570 | SCV000295007 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Molecular Genetics Laboratory, |
RCV000238570 | SCV000540764 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | |
U4M - |
RCV000238570 | SCV000583748 | pathogenic | Hypercholesterolemia, familial, 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
Iberoamerican FH Network | RCV000238570 | SCV000748089 | uncertain significance | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
Institute of Human Genetics, |
RCV000238570 | SCV001934255 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2020-10-20 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002444669 | SCV002677490 | likely pathogenic | Cardiovascular phenotype | 2024-09-26 | criteria provided, single submitter | clinical testing | The p.F282L variant (also known as c.846C>A), located in coding exon 6 of the LDLR gene, results from a C to A substitution at nucleotide position 846. The phenylalanine at codon 282 is replaced by leucine, an amino acid with highly similar properties. This variant, which was also known as p.F261L, was reported in multiple individuals with features consistent with familial hypercholesterolemia (FH) (Dušková L et al. Atherosclerosis, 2011 May;216:139-45; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8; Galaska R et al. J Atheroscler Thromb, 2016 May;23:588-95; Corral P et al. Atherosclerosis, 2018 Oct;277:256-261; Gaska R et al. PLoS One, 2018 Dec;13:e0209229; Saracoglu E et al. Echocardiography, 2018 Sep;35:1289-1299; Pajkowski M et al. Microvasc Res, 2021 Nov;138:104216; Leren TP et al. Atherosclerosis, 2021 Apr;322:61-66; Diboun I et al. Front Genet, 2022 Jul;13:927504; Noto D et al. Atherosclerosis, 2022 Apr;347:63-67). In an assay testing LDLR function, this variant showed a functionally abnormal result (Thormaehlen AS et al. PLoS Genet, 2015 Feb;11:e1004855). This amino acid position is highly 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. |
Gene |
RCV000161969 | SCV002762299 | likely pathogenic | not provided | 2022-11-25 | criteria provided, single submitter | clinical testing | Observed in individuals with familial hypercholesterolemia in published literature (Dukov et al., 2011; Do et al., 2015; Corral et al., 2018; Kose et al., 2020; Leren et al., 2021; Noto et al., 2022); Published functional studies demonstrate a damaging effect with reduced LDL-uptake (Thormaehlen et al., 2015); 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; This variant is associated with the following publications: (PMID: 25647241, 22698793, 21310417, 30270055, 26666465, 25487149, 32829317, 23833242, 33740630, 35339733) |
Institute of Human Genetics Munich, |
RCV000238570 | SCV002764774 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2021-05-27 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000161969 | SCV002822507 | likely pathogenic | not provided | 2022-11-01 | criteria provided, single submitter | clinical testing | LDLR: PM2, PS3:Moderate, PS4:Moderate |
Labcorp Genetics |
RCV003741152 | SCV004457930 | pathogenic | Familial hypercholesterolemia | 2023-06-24 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LDLR function (PMID: 25647241). 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. ClinVar contains an entry for this variant (Variation ID: 183098). This missense change has been observed in individuals with hypercholesterolemia (PMID: 21310417, 30270055, 30592719, 33740630, 35339733). This variant is present in population databases (rs730882090, gnomAD 0.0009%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 282 of the LDLR protein (p.Phe282Leu). |
All of Us Research Program, |
RCV000238570 | SCV004842746 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2023-12-15 | criteria provided, single submitter | clinical testing | This variant has been reported in multiple individuals with familial hypercholesterolemia (PMID: 34182004, 30592719, 22698793, 26666465, 29870584, 30270055, 35910211). Functional studies suggest that this variant results in a deleterious effect to the protein that is sufficient to be disease-causing (PMID: 25647241). This variant is present in 1/251430 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is predicted to be deleterious by in silico analysis. |
Clinical Genetics Laboratory, |
RCV000161969 | SCV005198649 | pathogenic | not provided | 2022-12-19 | criteria provided, single submitter | clinical testing | |
Dept. |
RCV000161969 | SCV000189544 | not provided | not provided | no assertion provided | in vitro | ||
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000238570 | SCV000606246 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |