rs28941776
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.1646G>A(p.Gly549Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G549?) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
LDLR
NM_000527.5 missense
NM_000527.5 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 9.79
Genes affected
LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 20 ACMG points.
PS1
Transcript NM_000527.5 (LDLR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
In a repeat LDL-receptor class B 4 (size 43) in uniprot entity LDLR_HUMAN there are 54 pathogenic changes around while only 5 benign (92%) in NM_000527.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-11116151-TGG-TC is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.996
PP5
Variant 19-11116153-G-A is Pathogenic according to our data. Variant chr19-11116153-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11116153-G-A is described in Lovd as [Pathogenic]. Variant chr19-11116153-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.1646G>A | p.Gly549Asp | missense_variant | 11/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LDLR | ENST00000558518.6 | c.1646G>A | p.Gly549Asp | missense_variant | 11/18 | 1 | NM_000527.5 | ENSP00000454071 | P3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251466Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135910
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GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461654Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17AN XY: 727118
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:32Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:20
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1988 | - - |
| Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
| Likely pathogenic, criteria provided, single submitter | research | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | Mar 01, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Feb 11, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
| Likely pathogenic, 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 | Dec 16, 2016 | subjects mutated among 2600 FH index cases screened = 4 , family member = 1 with co-segregation / FH-Palermo, 2% LDLR activity / Software predictions: Damaging - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | May 09, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Likely pathogenic, no assertion criteria provided | research | Iberoamerican FH Network | Mar 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 05, 2024 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation | Nov 05, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II | May 24, 2021 | Reduced activity, in stimulated T-lymphocytes and EBV-transformed B-lymphocytes. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 04, 2020 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 24, 2022 | PS3, PM1, PM5, PP2, PP3, PP5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 15, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 21, 2024 | Criteria applied: PS4,PM5_STR,PM2,PP3 - |
not provided Pathogenic:6Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 23, 2020 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 02, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2023 | LDLR: PM1:Strong, PM5, PS3:Moderate, PS4:Moderate - |
| not provided, no classification provided | in vitro | Dept. of Genetics and Pharmacogenomics, Merck Research Labs | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 30, 2021 | 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) - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jan 02, 2024 | - - |
Familial hypercholesterolemia Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 01, 2023 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Aug 06, 2018 | 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 25, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 17, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 17, 2024 | 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. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 02, 2022 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.;.;.;H
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D
Polyphen
D;.;.;.;.;.
Vest4
MutPred
Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;.;.;Loss of sheet (P = 0.1158);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at