Submissions for variant NM_000527.5(LDLR):c.1646G>A (p.Gly549Asp)

Total submissions: 33

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000003886	SCV000295560	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000003886	SCV000484682	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000003886	SCV000503381	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 4 , family member = 1 with co-segregation / FH-Palermo, 2% LDLR activity / Software predictions: Damaging
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000003886	SCV000540828	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000587938	SCV000544685	pathogenic	Familial hypercholesterolemia	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 549 of the LDLR protein (p.Gly549Asp). This variant is present in population databases (rs28941776, gnomAD 0.005%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 23375686, 25487149). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Italian ancestry (PMID: 23375686, 25487149). This variant is also known as p.Glu528Asp. ClinVar contains an entry for this variant (Variation ID: 3698). 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 affects LDLR function (PMID: 25647241). For these reasons, this variant has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000003886	SCV000583858	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000003886	SCV000588600	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000003886	SCV000607619	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587938	SCV000697207	pathogenic	Familial hypercholesterolemia	2017-03-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000003886	SCV000894176	pathogenic	Hypercholesterolemia, familial, 1	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000587938	SCV001346737	pathogenic	Familial hypercholesterolemia	2023-09-01	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 549 of the LDLR protein. This variant is also known as p.Gly528Asp in the mature protein and as FH Genoa and FH Palermo-1 in the literature. This variant alters a conserved glycine residue in the fourth LDLR type B repeat of the EGF precursor homology domain of the LDLR protein (a.a. 529 - 572), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tool suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). High throughput assays and functional studies with heterologous cells and homozygous patient fibroblasts have shown that this variant results in defective LDL transport/uptake and retains <2% LDLR activity compared to wild type (PMID: 1301956, 25647241, 31106925). Heterozygous patient cells showed 35-65% LDLR activity compared to wild type (PMID: 21865347). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 9544850, 11810272, 15241806, 21865347, 22371747, 23375686, 31106925) and is particularly common in Greek (PMID: 8683740) and Italian populations (PMID: 23375686). This variant has been identified in 6/246260 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000003886	SCV001433282	pathogenic	Hypercholesterolemia, familial, 1	2020-02-11	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000587938	SCV001435010	pathogenic	Familial hypercholesterolemia	2018-08-06	criteria provided, single submitter	clinical testing	The c.1646G>A (p.Gly549Asp) variant has been reported in multiple unrelated patients with familial hypercholesterolemia (PMID 1301956,9259195, 9544850, 11810272, 15199436, 15241806, 19837725, 21865347, 23375686) or myocardial infarction (PMID 25487149). A functional study reported the mutant LDLR protein retains less than 2 percent receptor activity compared to wild type LDLR protein (PMID 1301956) and the variant is classified as 'disruptive' through systematic cell-based phenotyping (PMID 25647241). Therefore, this c.1646G>A (p.Gly549Asp) variant is classified as pathogenic.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000003886	SCV001653643	pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing	Reduced activity, in stimulated T-lymphocytes and EBV-transformed B-lymphocytes.
Mayo Clinic Laboratories, Mayo Clinic	RCV000161997	SCV001715493	pathogenic	not provided	2020-07-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000161997	SCV001782225	pathogenic	not provided	2021-12-30	criteria provided, single submitter	clinical testing	Also reported as FH Genoa, FH Palermo-1, and G528D due to alternate nomenclature; Published functional studies demonstrate a damaging effect with abnormal LDL transport/uptake and significantly reduced receptor activity (Hobbs et al., 1990; Romano et al., 2011; Thormaehlen et al., 2015; Rodriguez-Jimenez et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID#3698; ClinVar); This variant is associated with the following publications: (PMID: 21925044, 29874871, 28965616, 33093846, 23375686, 25487149, 25647241, 25525159, 21865347, 28391899, 20045108, 2088165, 9259195, 9544850, 11317361, 15199436, 15241806, 19446849, 19717150, 19837725, 22371747, 21310417, 25463123, 27578104, 31447099, 31106925, 34040191, 32977124, 32041611, 32770674, 33740630, 34037665)
Revvity Omics, Revvity	RCV000003886	SCV002017106	pathogenic	Hypercholesterolemia, familial, 1	2022-02-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000161997	SCV002046853	pathogenic	not provided	2020-12-23	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals affected with familial hypercholesterolemia (FH) (PMIDs: 9259195 (1997), 9544850 (1998), 9974426 (1999), 11317361 (2001), 12436241 (2002), 15199436 (2004), 15241806 (2004), 19837725 (2010), 22371747 (2010), and 23375686 (2013)). In addition, functional analyses report that this variant results in decreased LDLR protein activity, with <2% residual activity in homozygous individuals and a mean residual activity of 50% in heterozygous individuals (PMID: 1301956 (1992), 21865347 (2011), and 25647241 (2015)). Therefore, the variant is classified as pathogenic.
Ambry Genetics	RCV002390088	SCV002704025	pathogenic	Cardiovascular phenotype	2022-05-02	criteria provided, single submitter	clinical testing	The p.G549D pathogenic mutation (also known as c.1646G>A), located in coding exon 11 of the LDLR gene, results from a G to A substitution at nucleotide position 1646. The glycine at codon 549 is replaced by aspartic acid, an amino acid with similar properties. This alteration, also referred to as p.G528D, has been shown to reduce LDLR activity to 35-65% of normal levels in vitro (Romano M et al. J Lipid Res. 2011;52(11):2095-100) and prevent LDLR endocytosis (Thormaehlen AS et al. PLoS Genet. 2015;11(2): e1004855). In addition, this mutation has been found to be a common pathogenic alteration in various familial hypercholesterolemia population cohorts (Traeger-Synodinos J et al. Hum Genet. 1998, Diakou M et al, Arch Med Sci 2010; 6(2):198-200, Bertolini S et al, Atherosclerosis 2013;227(2):342-8; Pirillo A et al. Atheroscler Suppl, 2017 Oct;29:17-24), possibly stemming from a common ancestor (Bertolini S et al. Arterioscler Thromb Vasc Biol. 2000;20(9):E41-52). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
CeGaT Center for Human Genetics Tuebingen	RCV000161997	SCV003918064	pathogenic	not provided	2024-11-01	criteria provided, single submitter	clinical testing	LDLR: PM1:Strong, PM5, PS3:Moderate, PS4:Moderate
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000003886	SCV004013975	pathogenic	Hypercholesterolemia, familial, 1	2022-10-24	criteria provided, single submitter	clinical testing	PS3, PM1, PM5, PP2, PP3, PP5
Genetics and Molecular Pathology, SA Pathology	RCV000003886	SCV004175360	pathogenic	Hypercholesterolemia, familial, 1	2022-05-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000003886	SCV004822484	pathogenic	Hypercholesterolemia, familial, 1	2024-01-05	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 549 of the LDLR protein. This variant is also known as p.Gly528Asp in the mature protein and as FH Genoa and FH Palermo-1 in the literature. This variant alters a conserved glycine residue in the fourth LDLR type B repeat of the EGF precursor homology domain of the LDLR protein (a.a. 529 - 572), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tool suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). High throughput assays and functional studies with heterologous cells and homozygous patient fibroblasts have shown that this variant results in defective LDL transport/uptake and retains <2% LDLR activity compared to wild type (PMID: 1301956, 25647241, 31106925). Heterozygous patient cells showed 35-65% LDLR activity compared to wild type (PMID: 21865347). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 9544850, 11810272, 15241806, 21865347, 22371747, 23375686, 31106925) and is particularly common in Greek (PMID: 8683740) and Italian populations (PMID: 23375686). This variant has been identified in 6/246260 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000003886	SCV004848439	pathogenic	Hypercholesterolemia, familial, 1	2020-09-04	criteria provided, single submitter	clinical testing	The p.Gly549Asp variant in LDLR has been reported in many individuals with familial hypercholesterolemia and has been shown to segregate in >10 affected family members (Marino 1999 PMID:10338098, Dedoussis 2004 PMID:14974088, Diakou 2010 PMID:22371747, Bertolini 2013 PMID:23375686, Thormaehlen 2015 PMID:25647241, Benito-Vicente 2018 PMID:29874871). This variant is known as a common pathogenic variant in the Italian population, and is referred to as FH Genoa and p.Gly528Asp in the literature. It has been reported in ClinVar (Variation ID 3698). An in vitro functional study indicates that this variant is associated with abnormal transport of LDL receptor protein in which the receptor mislocalizes endoplasmatic reticulum (ER)-like membranes (Benito-Vicente 2018 PMID:29874871). This variant has been identified in 0.005% (6/113752) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, for diseases with clinical variability or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP criteria applied: PS4, PP1_Strong, PP3, PS3_Supporting.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000161997	SCV005198658	pathogenic	not provided	2024-01-02	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000003886	SCV005368412	pathogenic	Hypercholesterolemia, familial, 1	2024-08-21	criteria provided, single submitter	clinical testing	Criteria applied: PS4,PM5_STR,PM2,PP3
OMIM	RCV000003886	SCV000024051	pathogenic	Hypercholesterolemia, familial, 1	1988-11-01	no assertion criteria provided	literature only
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161997	SCV000189572	not provided	not provided		no assertion provided	in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000003886	SCV000606474	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000003886	SCV000733824	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	clinical testing
Iberoamerican FH Network	RCV000003886	SCV000748175	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000161997	SCV001925125	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000587938	SCV002086430	pathogenic	Familial hypercholesterolemia	2020-08-25	no assertion criteria provided	clinical testing