rs144614838
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3PP4PS4PP1_Strong
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1432G>A (p.Gly478Arg) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_strong, PS4, 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: PP1_strong - variant segregates with FH phenotype in 10 informative meiosis from 4 families from 2 labs:- Laboratory of Genetics and Molecular Cardiology - Data from 1 family: 2 relatives positive for variant with LDL-C >75th percentile, 1 relative negative for variant with LDL-C <50th percentile;- Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge - Data from 3 families. F1: 3 relatives with the phenotype are positive for the variant plus 1 relative without the phenotype is negative for the variant. F2: 1 relative with the phenotype and positive for the variant plus 1 relative without the phenotype is negative for the variant. F3: 1 relative with the phenotype is positive for the variant.so PP1_Strong is metPS4 - variant meets PM2 and was identified in at least 11 unrelated index cases who fulfill clinical FH criteria from different labs:- 1 case with Simon-Broome criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); - 1 case with DLCN score >= 6 from Color Health, Inc; - 4 unrelated cases with DLCN score >= 6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); - 4 unrelated cases with Simon-Broome criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge; - 1 case with DLCN score >= 6 from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory),so PS4 is metPM2 - PopMax MAF = 0.0001234 (0.01234%) in African/African-American exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met.PP3 - REVEL = 0.985. It is above 0.75, so PP3 is met.PP4 - variant meets PM2 and was identified in at least 11 unrelated index cases who fulfill clinical FH criteria from different labs (see details in PS4), so PP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023495/MONDO:0007750/013
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
LDLR
NM_000527.5 missense
NM_000527.5 missense
Scores
17
1
1
Clinical Significance
Conservation
PhyloP100: 8.03
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 12 ACMG points.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
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.1432G>A | p.Gly478Arg | 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.1432G>A | p.Gly478Arg | missense_variant | 10/18 | 1 | NM_000527.5 | ENSP00000454071 | P3 |
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 152120Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251112Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135808
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461736Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5AN XY: 727182
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GnomAD4 genome 0.0000263 AC: 4AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74292
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:21Uncertain:5
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:11Uncertain:4
| Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation | Nov 05, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Sep 19, 2017 | This c.1432G>A (p.Gly478Arg) variant in the LDLR gene has been reported in multiple patients with familial hypercholesterolemia (PMID: 1301956, 7573037, 9763532, 11810272). Functional studies have indicated that the p.Gly478Arg variant LDLR protein has 2-5% receptor activity compared to wild-type LDLR protein (PMID: 1301956). The c.1432G>A variant is extremely rare in the general population and glycine at position 478 of the LDLR protein is highly evolutionarily conserved. The c.1432G>A (p.Gly478Arg) variant in the LDLR gene is classified as likely pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | research | Cardiovascular Biomarker Research Laboratory, Mayo Clinic | Aug 31, 2015 | MAF =<0.3%, likely pathogenic based on the integrative in-silico score, DLCN criteria >=3; LDL-C >=160 mg/dL, previously reported as P/LP in the literature - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 20, 2023 | This missense variant replaces glycine with arginine at codon 478 and alters a conserved glycine residue in the second LDLR type B repeat of the EGF precursor homology domain of the LDLR protein (a.a. 439-485) where pathogenic missense variants are found enriched (ClinVar-LDLR). This variant is also known as p.Gly457Arg in the mature protein sequence and as FH New York-2 and FH Fin-9 in the literature. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes a defect in protein transport and recycling, and a decreased LDLR activity (PMID: 1301956, 32695144). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 1301956, 7573037, 9763532, 11810272, 22883975, 25618577, 32143996, 32220565, 32331935; Color internal data). In addition, this variant has been shown to segregate with disease in six affected individuals from two families and was absent in four unaffected family members (PMID: 24627126), as well as in 10 informative meiosis from 4 unpublished families (ClinVar variation ID: 161277; accession ID: SCV002506334.1). This variant has been identified in 7/251112 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 | Revvity Omics, Revvity | Sep 26, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | research | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | 0/208 non-FH alleles; 0/50 normolipidemic individuals; 0/100 healthy control individuals - |
| Uncertain significance, 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 / FH-New-York-2, 5 to 15% LDLR activity/Software predictions: Conflicting - |
| Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
| Uncertain significance, criteria provided, single submitter | research | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | Mar 01, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Jun 27, 2008 | - - |
| Pathogenic, no assertion criteria provided | research | Medical Laboratory Center, Huzhou Maternal and Child Health Hospital | - | - - |
| Pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Dec 14, 2021 | The NM_000527.5(LDLR):c.1432G>A (p.Gly478Arg) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_strong, PS4, 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: PP1_strong - variant segregates with FH phenotype in 10 informative meiosis from 4 families from 2 labs: - Laboratory of Genetics and Molecular Cardiology - Data from 1 family: 2 relatives positive for variant with LDL-C >75th percentile, 1 relative negative for variant with LDL-C <50th percentile; - Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge - Data from 3 families. F1: 3 relatives with the phenotype are positive for the variant plus 1 relative without the phenotype is negative for the variant. F2: 1 relative with the phenotype and positive for the variant plus 1 relative without the phenotype is negative for the variant. F3: 1 relative with the phenotype is positive for the variant. so PP1_Strong is met PS4 - variant meets PM2 and was identified in at least 11 unrelated index cases who fulfill clinical FH criteria from different labs: - 1 case with Simon-Broome criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); - 1 case with DLCN score >= 6 from Color Health, Inc; - 4 unrelated cases with DLCN score >= 6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); - 4 unrelated cases with Simon-Broome criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge; - 1 case with DLCN score >= 6 from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory), so PS4 is met PM2 - PopMax MAF = 0.0001234 (0.01234%) in African/African-American exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PP3 - REVEL = 0.985. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in at least 11 unrelated index cases who fulfill clinical FH criteria from different labs (see details in PS4), so PP4 is met. - |
| Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Familial hypercholesterolemia Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 19, 2023 | Variant summary: LDLR c.1432G>A (p.Gly478Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251112 control chromosomes (gnomAD). c.1432G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Koivisto_1995, Chiou_2010, Chiou_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20538126, 28502495, 7573037). 19 ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=4), likely pathogenic (n=10) and pathogenic (n=5, including one expert panel, ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel). Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Jan 26, 2023 | The c.1432G>A (p.Gly478Arg) variant in the LDLR gene is located on the exon 10 and is predicted to replace the glycine with arginine at codon 478 (p.Gly478Arg). The variant has been reported in more than 10 unrelated individuals affected with familial hypercholesterolemia (PMIDs: 27206935, 27680772, 32331935). Another variant disrupting the same amino acid (p.Gly478Glu) has been interpreted as likely pathogenic (ClinVar ID: 440642). The p.Gly478Arg variant has been reported in ClinVar (ID: 161277) and reviewed as a pathogenic variant by the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel. This variant has been observed by different laboratories to segregate with disease in over 10 meioses of 4 families according to the ClinGen Expert Panel. This variant is rare in the general population according to gnomAD (7/251112). Computational prediction algorithms suggest a deleterious impact (REVEL score 0.985). Therefore, the c.1432G>A (p.Gly478Arg) variant of LDLR has been classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 478 of the LDLR protein (p.Gly478Arg). This variant is present in population databases (rs144614838, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 17087781, 17765246, 21376320, 22353362, 23064986, 27206935, 30592178; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gly457Arg. ClinVar contains an entry for this variant (Variation ID: 161277). 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%. This variant disrupts the p.Gly478 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 27824480), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 13, 2023 | This missense variant replaces glycine with arginine at codon 478 and alters a conserved glycine residue in the second LDLR type B repeat of the EGF precursor homology domain of the LDLR protein (a.a. 439-485) where pathogenic missense variants are found enriched (ClinVar-LDLR). This variant is also known as p.Gly457Arg in the mature protein sequence and as FH New York-2 and FH Fin-9 in the literature. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes a defect in protein transport and recycling, and a decreased LDLR activity (PMID: 1301956, 32695144). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 1301956, 7573037, 9763532, 11810272, 22883975, 25618577, 32143996, 32220565, 32331935; Color internal data). In addition, this variant has been shown to segregate with disease in six affected individuals from two families and was absent in four unaffected family members (PMID: 24627126), as well as in 10 informative meiosis from 4 unpublished families (ClinVar variation ID: 161277; accession ID: SCV002506334.1). This variant has been identified in 7/251112 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 12, 2020 | - - |
not provided Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Nov 20, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2024 | Published functional studies suggest impaired LDLR localization and LDL uptake (PMID: 32695144); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as FH New York-2, FH Finn-9, and G457R; This variant is associated with the following publications: (PMID: 23064986, 24055113, 25637381, 30592178, 15199436, 11810272, 18325082, 27680772, 17765246, 15556092, 28145427, 19118540, 9763532, 20538126, 29245966, 22883975, 29261184, 29874871, 1301956, 24507775, 27206935, 21376320, 19318025, 30526649, 17087781, 7573037, 37409534, 36226792, 35130036, 35913489, 35480308, 33955087, 32220565, 8535447, 29292049, 31447099, 32331935, 33994402, 32143996, LinJL2022, 33740630, 34037665, 28126585, 32695144) - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Sep 24, 2019 | - - |
Homozygous familial hypercholesterolemia Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 26, 2019 | The p.Gly478Arg (also called p.Gly457Arg) variant in LDLR has been reported in the heterozygous state in >15 individuals with hypercholesterolemia, and segregated with disease in at least 4 relatives from these families (Hobbs 1992, Koivisto 1995, Bourbon 2008, Alonso 2009, Ahmad 2012, Hooper 2012, Lange 2014, Safaro 2017, ClinVar: Variation ID 161277). The variant has also been reported in two individuals who were compound heterozygous for this variant and a second variant in LDLR (Mak 1998, Chiou 2010). Additionally, another nucleotide change (c.1432G>C) leading to the same amino acid change has been reported in 2 individuals with FH, one of whom was homozygous for the variant (Fouchier 2005, Widhalm 2017). In vitro functional studies provide some evidence that the p.Gly478Arg variant may impact protein function (Hobbs 1992). This variant has been also been identified in 2/17246 East Asian chromosomes and 2/16208 African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Gly478Arg 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, the p.Gly478Arg variant is likely pathogenic. The ACMG/AMP criteria applied: PS4, PP1, PP3, PS3_Supporting. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 23, 2024 | The p.G478R pathogenic mutation (also known as c.1432G>A), located in coding exon 10 of the LDLR gene, results from a G to A substitution at nucleotide position 1432. The glycine at codon 478 is replaced by arginine, an amino acid with dissimilar properties. This variant (also described as legacy p.G457R) has been described in several patients with familial hypercholesterolemia (FH) (Koivisto UM et al. Am J Hum Genet. 1995;57:789-97; Mak YT et al. Arterioscler Thromb Vasc Biol. 1998;18:1600-5; Bourbon M et al. Atherosclerosis. 2008;196:633-42; Chiou KR et al. J Clin Lipidol. 2016;10(3):490-6; Tada H et al. J Clin Lipidol Dec;12:397-402.e2; Hartgers ML et al. J Clin Lipidol Dec;12:390-396.e8; Ambry internal data). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Lo Surdo P et al. EMBO Rep., 2011 Dec;12:1300-5). In an assay testing LDLR function, this variant showed a functionally abnormal result (Graça R et al. JACC Basic Transl Sci, 2023 Aug;8:1010-1021). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. - |
Hypercholesterolemia Uncertain:1
| Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
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
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 catalytic residue at A480 (P = 0.111);Loss of catalytic residue at A480 (P = 0.111);.;.;.;Loss of catalytic residue at A480 (P = 0.111);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at