Submissions for variant NM_000527.5(LDLR):c.846C>A (p.Phe282Leu)

gnomAD frequency: 0.00001  dbSNP: rs730882090

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	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-LOVD, British Heart Foundation	RCV000238570	SCV000295007	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000238570	SCV000540764	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	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, University of Leipzig Medical Center	RCV000238570	SCV001934255	likely pathogenic	Hypercholesterolemia, familial, 1	2020-10-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002444669	SCV002677490	uncertain significance	Cardiovascular phenotype	2020-03-11	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, and is located in the ligand binding domain. This variant has been reported in hypercholesterolemia cohorts; however, clinical details were limited (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). This variant was also detected in an individual with history of myocardial infarction who had normal LDL-C levels, and limited functional studies suggested some impact on LDL uptake (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Do R et al. Nature, 2015 Feb;518:102-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	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, Klinikum Rechts Der Isar, TU München	RCV000238570	SCV002764774	likely pathogenic	Hypercholesterolemia, familial, 1	2021-05-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000161969	SCV002822507	likely pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	LDLR: PM2, PS3:Moderate, PS4:Moderate
Invitae	RCV003741152	SCV004457930	pathogenic	Familial hypercholesterolemia	2023-06-24	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 183098). 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. 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, National Institutes of Health	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.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161969	SCV000189544	not provided	not provided		no assertion provided	in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238570	SCV000606246	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research