rs28942080
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS4PP1_StrongPM2PP3PP4PS3_ModeratePM3
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR): c.1567G>A (p.Val523Met) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PP1_Strong, PM2, PM3, PS3_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00003266 (0.003%) in East Asian (gnomAD v2.1.1). PP3: REVEL = 0.917. PS3_Moderate: Functional studies: PMID 1301956 (Hobbs et al., 1992), Level 2 assay using homozygous patients' fibroblasts, 125I-LDL assays - 15-30% LDLR activity (but all cycle was tested) // PMID 9974426 (Bertolini et al., 1999), Level 2 assay using homozygous patient fibroblast, 125I-LDL assays - 25% LDLR activity, (mention of testing LDL binding, internalization, and degradation) // PMID 21865347 (Romano et al., 2011), Level 3 assays using heterozygous patients' Epstein-Barr virus transformed lymphocytes and FACS assays - 30-40% LDLR activity. // PMID 25647241 (Thormaehlen et al., 2015), functional studies using HeLa cells and alternative microscopy assay showed that the LDLR activity is decreased compared to WT and was considered as "disruptive" ------ Overall, functional studies (PMID 1301956, 9974426, 21865347) show an activity below 70% of wild-type, consistent with damaging effect and PS3 is met.PS4, PP4: Variant meets PM2 and is identified in at least 22 unrelated cases, 2 fulfilling Simon-Broome criteria (GeneDx) and 20 with DLCN score >=6 (Service de Biochimie et de Biologie Moléculaire, France; Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca Department of Translational and Precision Medicine, Italy; Robarts Research Institute, Canada). PP1_Strong: variant segregates with FH phenotype in 14 informative meioses in 8 families from different labs (Service de Biochimie et de Biologie Moléculaire, France; Laboratory of Genetics and Molecular Cardiology, Brazil; Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca Department of Translational and Precision Medicine, Italy): 11 affected family members have the variant and 3 non-affected family members do not have the variant. PM3: 1 case reported from Service de Biochimie et de Biologie Moléculaire, France (homozygous and LDL-cholesterol 12 mmol/L at 4 years old). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023525/MONDO:0007750/013
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
LDLR
NM_000527.5 missense
NM_000527.5 missense
Scores
12
5
2
Clinical Significance
Conservation
PhyloP100: 8.02
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 16 ACMG points.
PS3
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.1567G>A | p.Val523Met | missense_variant | 10/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LDLR | ENST00000558518.6 | c.1567G>A | p.Val523Met | missense_variant | 10/18 | 1 | NM_000527.5 | ENSP00000454071.1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251336Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135872
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GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461630Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10AN XY: 727128
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GnomAD4 genome 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74346
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:27Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:18
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 27, 2014 | - - |
| Likely pathogenic, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
| 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 = 2 , family members = 4 with co-segregation / FH-Koweit-Bari,15 to 30% LDLR Activity/Software predictions: Conflicting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Apr 29, 2019 | - - |
| Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Jan 23, 2013 | - - |
| Likely pathogenic, criteria provided, single submitter | research | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | Mar 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 21, 2022 | - - |
| 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 | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
| Likely pathogenic, criteria provided, single submitter | research | Iberoamerican FH Network | 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 | clinical testing | Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
| Pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Jan 27, 2023 | The NM_000527.5(LDLR): c.1567G>A (p.Val523Met) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PP1_Strong, PM2, PM3, PS3_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00003266 (0.003%) in East Asian (gnomAD v2.1.1). PP3: REVEL = 0.917. PS3_Moderate: Functional studies: PMID 1301956 (Hobbs et al., 1992), Level 2 assay using homozygous patients' fibroblasts, 125I-LDL assays - 15-30% LDLR activity (but all cycle was tested) // PMID 9974426 (Bertolini et al., 1999), Level 2 assay using homozygous patient fibroblast, 125I-LDL assays - 25% LDLR activity, (mention of testing LDL binding, internalization, and degradation) // PMID 21865347 (Romano et al., 2011), Level 3 assays using heterozygous patients' Epstein-Barr virus transformed lymphocytes and FACS assays - 30-40% LDLR activity. // PMID 25647241 (Thormaehlen et al., 2015), functional studies using HeLa cells and alternative microscopy assay showed that the LDLR activity is decreased compared to WT and was considered as "disruptive" ------ Overall, functional studies (PMID 1301956, 9974426, 21865347) show an activity below 70% of wild-type, consistent with damaging effect and PS3 is met. PS4, PP4: Variant meets PM2 and is identified in at least 22 unrelated cases, 2 fulfilling Simon-Broome criteria (GeneDx) and 20 with DLCN score >=6 (Service de Biochimie et de Biologie Moléculaire, France; Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca Department of Translational and Precision Medicine, Italy; Robarts Research Institute, Canada). PP1_Strong: variant segregates with FH phenotype in 14 informative meioses in 8 families from different labs (Service de Biochimie et de Biologie Moléculaire, France; Laboratory of Genetics and Molecular Cardiology, Brazil; Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca Department of Translational and Precision Medicine, Italy): 11 affected family members have the variant and 3 non-affected family members do not have the variant. PM3: 1 case reported from Service de Biochimie et de Biologie Moléculaire, France (homozygous and LDL-cholesterol 12 mmol/L at 4 years old). - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Mar 16, 2018 | - - |
| 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. - |
Familial hypercholesterolemia Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 30, 2019 | This missense variant (also known as p.Val502Met in the mature protein and as FH Kuwait, FH Bari-2) replaces valine with methionine at codon 523 in the third LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant causes LDLR recycling defect (PMID: 2088165) and results in a significantly reduced LDLR activity in cells from homozygous individuals (PMID: 9974426). This variant has been reported in over 15 European individuals affected with familial hypercholesterolemia (PMID: 7616128, 12436241, 15241806, 20045108, 26892515), including several homozygous and compound heterozygous individuals (PMID: 9974426, 30795984). This variant has been identified in 3/251336 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 09, 2016 | Variant summary: The LDLR c.1567G>A (p.Val523Met) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/120764 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0010005). The variant has been reported in numerous affected individuals in the literature in the homozygous and compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Val523Met variant in LDLR has been reported in at least 15 individuals with familial hypercholesterolemia (PMID: 15241806, 25463123, 15199436, 9974426, 7616128, 2088165, 21310417, 26892515, 12436241), and has been identified in 0.003% (1/30616) of South Asian chromosomes and 0.002% (2/113644) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28942080). This variant has also been reported in ClinVar as pathogenic or likely pathogenic (Variation ID: 3696). In vitro functional studies provide some evidence that the p.Val523Met variant may slightly impact protein function (PMID: 25647241, 21865347). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PP3, PS3_supporting (Richards 2015). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 05, 2024 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 523 of the LDLR protein (p.Val523Met). This variant is present in population databases (rs28942080, gnomAD 0.003%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 2088165, 14974088, 15256764, 21310417, 21865347, 22294733, 23375686, 25463123, 27765764). This variant is also known as V502M. ClinVar contains an entry for this variant (Variation ID: 3696). 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: 25647241). This variant disrupts the p.Val523 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 20809525), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:3Other:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Nov 29, 2022 | - - |
| not provided, no classification provided | in vitro | Dept. of Genetics and Pharmacogenomics, Merck Research Labs | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Homozygous familial hypercholesterolemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 28, 2020 | The p.Val523Met variant in LDLR (also referred as p.Val502Met, FH Kuwait, and FH Bari-2) has been reported in >100 heterozygous individuals with hypercholesterolemia as well as in at least 3 homozygous individuals and 3 compound heterozygous individuals with homozygous familial hypercholesterolemia (Hobbs 1990, Tichy 2012, Bertolini 2013, Wang 2016, Sánchez-Hernández 2016, Pirillo 2017). This variant also segregated with homozygous familial hypercholesterolemia in 1 homozygous relative (Bertolini 2013). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 3696) and has been identified in 0.003% (1/30782) of South Asian and 0.002% (2/111654) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the heterozygous p.Val523Met variant may impact protein function (Romano 2011). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PS4, PM2, PS3_Supporting, PM3_Strong. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 06, 2024 | The c.1567G>A (p.V523M) alteration is located in coding exon 10 of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 1567, causing the valine (V) at amino acid position 523 to be replaced by a methionine (M). Based on data from gnomAD, the A allele has an overall frequency of 0.001% (3/251336) total alleles studied. The highest observed frequency was 0.003% (1/30616) of South Asian alleles. This alteration has been reported in the homozygous and heterozygous states in multiple individuals with familial hypercholesterolemia from various ethnic groups (Hobbs, 1992; Lombardi, 1995; Bertolini, 1999; Amsellem, 2002; Leren, 2004; Mozas, 2004; Dušková, 2011; Mollaki, 2014; Sharifi, 2016; Luirink, 2019). This amino acid position is well conserved in available vertebrate species. Internal structural analysis indicates this alteration to be structurally disruptive (Lo Surdo, 2011). In addition, a number of studies have reported this alteration to attenuate LDLR activity (Hobbs, 1992; Bertolini, 1999; Romano, 2011). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
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
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;N
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
D;.;.;.;.;.
Vest4
MutPred
Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;.;.;Loss of sheet (P = 0.0817);
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