rs373822756
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 18P and 4B. PS4PP1_StrongBS4PM2PP3PP4PS3_ModeratePM1PM3
This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR): c.662A>G (p.Asp221Gly) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_strong, PS3_moderate, PS4, PM1, PM2, PM3, PP3, PP4 and BS4) 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 92 informative meiosis in at least 37 families from different labs (Robarts Research Institute; Laboratory of Genetics and Molecular Cardiology, University of São Paulo; Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)): 55 affected family members have the variant, 37 unaffected family members don’t have the variant.PS3_moderate - PMID:9974426 - Level 2 assay - Homozygous patients' fibroblasts, 125I-LDL assays: 8% LDLR activity; PMID:25647241 - Level 3 assay - Heterologous cells (HeLa), CLSM assay: most of mutant LDLR is in ER, LDLR activity decreased compared to WT - considered as disruptive.PS4 - Variant meets PM2. Variant identified in 48 unrelated index cases (2 cases with DLCN≥6 from Robarts Research Institute; 21 cases (13 patients with DLCN≥6, and 8 patients with possible FH (Simon Broome)) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 17 cases with possible/definite FH (Simon-Broome) from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 1 case with Possible FH (Simon-Broome) from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 5 cases with DLCN≥6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 2 cases with DLCN≥6 from Color Health, Inc.PM1 - Variant meets PM2 and is missense in exon 4.PM2 - PopMax MAF = 0.0001152 (0.01152%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1).PM3 - Index case from Ambry Genetics has LDL = 750 mg/dl and also LDLR c.2140+1G>T (pathogenic by these guidelines, confirmed to be in trans).PP3 - REVEL = 0.986.PP4 - Variant meets PM2. Identified in 48 FH cases from different labs (for list see PS4) with clinical Dutch Lipid Clinic Network Criteria score ≥ 6 or Simon-Broome possible/definite FH, after alternative causes of high cholesterol were excluded.BS4 - 30 nonsegregations in 12 families (Laboratory of Genetics and Molecular Cardiology, University of São Paulo).Variant has 2 Strong plus 4 Moderate plus 2 Supporting evidence codes towards Pathogenic, enough to classify as Pathogenic, and only 1 Strong evidence codes towards Benign. The Pathogenic criteria overwhelms the Benign criteria, so we are confident in classifying this variant as Pathogenic. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023739/MONDO:0007750/013
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
LDLR
NM_000527.5 missense
NM_000527.5 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 9.21
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 14 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.
PM1
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.
BS4
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.662A>G | p.Asp221Gly | missense_variant | 4/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LDLR | ENST00000558518.6 | c.662A>G | p.Asp221Gly | missense_variant | 4/18 | 1 | NM_000527.5 | ENSP00000454071.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.0000520 AC: 13AN: 249796Hom.: 0 AF XY: 0.0000812 AC XY: 11AN XY: 135548
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GnomAD4 exome AF: 0.0000274 AC: 40AN: 1459188Hom.: 0 Cov.: 33 AF XY: 0.0000303 AC XY: 22AN XY: 725462
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:31Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:19
| Pathogenic, criteria provided, single submitter | research | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | 0/190 non-FH alleles; 0/60 healthy control individuals - |
| Pathogenic, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Dec 12, 2009 | - - |
| 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 | - - |
| Pathogenic, criteria provided, single submitter | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | Jun 04, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
| Pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | May 30, 2022 | NM_000527.5(LDLR): c.662A>G (p.Asp221Gly) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_strong, PS3_moderate, PS4, PM1, PM2, PM3, PP3, PP4 and BS4) 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 92 informative meiosis in at least 37 families from different labs (Robarts Research Institute; Laboratory of Genetics and Molecular Cardiology, University of São Paulo; Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)): 55 affected family members have the variant, 37 unaffected family members don’t have the variant. PS3_moderate - PMID: 9974426 - Level 2 assay - Homozygous patients' fibroblasts, 125I-LDL assays: 8% LDLR activity; PMID: 25647241 - Level 3 assay - Heterologous cells (HeLa), CLSM assay: most of mutant LDLR is in ER, LDLR activity decreased compared to WT - considered as disruptive. PS4 - Variant meets PM2. Variant identified in 48 unrelated index cases (2 cases with DLCN≥6 from Robarts Research Institute; 21 cases (13 patients with DLCN≥6, and 8 patients with possible FH (Simon Broome)) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 17 cases with possible/definite FH (Simon-Broome) from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 1 case with Possible FH (Simon-Broome) from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 5 cases with DLCN≥6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 2 cases with DLCN≥6 from Color Health, Inc. PM1 - Variant meets PM2 and is missense in exon 4. PM2 - PopMax MAF = 0.0001152 (0.01152%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1). PM3 - Index case from Ambry Genetics has LDL = 750 mg/dl and also LDLR c.2140+1G>T (pathogenic by these guidelines, confirmed to be in trans). PP3 - REVEL = 0.986. PP4 - Variant meets PM2. Identified in 48 FH cases from different labs (for list see PS4) with clinical Dutch Lipid Clinic Network Criteria score ≥ 6 or Simon-Broome possible/definite FH, after alternative causes of high cholesterol were excluded. BS4 - 30 nonsegregations in 12 families (Laboratory of Genetics and Molecular Cardiology, University of São Paulo). Variant has 2 Strong plus 4 Moderate plus 2 Supporting evidence codes towards Pathogenic, enough to classify as Pathogenic, and only 1 Strong evidence codes towards Benign. The Pathogenic criteria overwhelms the Benign criteria, so we are confident in classifying this variant as Pathogenic. - |
| Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II | May 24, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant (also known as p.Asp200Gly in the mature protein) replaces aspartic acid with glycine at codon 221 located in the fifth LDLR type A repeat of the ligand binding domain of the LDLR protein. 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). A functional study has shown the mutant protein to exhibit loss of LDL uptake activity and to be defective for transport through the endoplasmic reticulum (PMID: 21865347). This variant has been identified in more than 100 individuals diagnosed with familial hypercholesterolemia from multiple European ethnicities (PMID: 1301956, 7649546, 9104431, 10208479, 10978268, 17765246, 20145306, 21310417, 32770674, 34037665, 35052492, 35626767) and is highly recurrent in the Northern Italian population (PMID: 10978268). This variant has been identified in 13/249796 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Asp221Asn and p.Asp221Tyr, are considered to be disease-causing (ClinVar variation ID: 226331 and 251356), suggesting that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. - |
| 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 = 12 , family members = 7 with co-segregation / FH-Padua / Software predictions: Damaging - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 13, 2024 | Criteria applied: PS4,PP1_STR,PS3_MOD,PM1,PM2,PM3,PP3,PP4,BS4 - |
| Pathogenic, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 09, 2023 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | - | - - |
| 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 | clinical testing | Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation | Nov 05, 2016 | Asp221 bind structural Ca2+. - |
| Pathogenic, criteria provided, single submitter | not provided | Institute of Human Genetics, University Hospital of Duesseldorf | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen | Sep 25, 2018 | The mutation occurs at the protein level at position 221 (position 200 of the mature protein) to exchange the amino acid aspartate for glycine. This change has already been described in the literature as the FH Padova-1 allele, detected in patients with familial hypercholesterolemia, and associated with elevated cholesterol and LDL-C levels. It leads to an almost complete loss of LDL receptor activity. We observed this variant in a patient with TC up to 380 mg/dl and LDL-C approx 310 mg/dl. PMID: 25647241, 23375686 - |
Familial hypercholesterolemia Pathogenic:6
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health | Aug 06, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Mar 01, 2019 | The c.662A>G (p.Asp221Gly) variant in the LDLR gene has been reported in multiple unrelated individuals affected with familial hypercholesterolemia (PMID 1301956, 11196104, 15241806, 20145306,23375686) and has also been reported in multiple myocardial infarction cases while absent from healthy controls (PMID 25487149). Independent functional studies demonstrated deleterious effect of the p.Asp221Gly variant (PMID 1301956, 25647241). Multiple algorithms predicted this change to be damaging. Therefore, this c.662A>G (p.Asp221Gly) variant in the LDLR gene is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 16, 2018 | Variant summary: LDLR c.662A>G (p.Asp221Gly) results in a non-conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was found in 13/245460 control chromosomes (0.00005296), which does not exceed the maximum expected allele frequency for a pathogenic variant in the LDLR gene (0.0013). The c.662A>G variant has been reported in the literature in numerous individuals affected with Familial Hypercholesterolemia. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal LDLR activity (Thormaehlen_2015). Several other variants that cause a change at Asp221 are associated with disease (e.g., D221N, D221Y, and D221V), suggesting the codon is critical for function. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All of these laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 221 of the LDLR protein (p.Asp221Gly). This variant is present in population databases (rs373822756, gnomAD 0.01%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 15523646, 23375686). 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: 2698793, 11196104, 15241806, 20236128, 25461735). This variant is also known as p.Asp200Gly. ClinVar contains an entry for this variant (Variation ID: 183092). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 28, 2023 | This missense variant (also known as p.Asp200Gly in the mature protein) replaces aspartic acid with glycine at codon 221 located in the fifth LDLR type A repeat of the ligand binding domain of the LDLR protein. 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). A functional study has shown the mutant protein to exhibit loss of LDL uptake activity and to be defective for transport through the endoplasmic reticulum (PMID: 21865347). This variant has been identified in more than 100 individuals diagnosed with familial hypercholesterolemia from multiple European ethnicities (PMID: 1301956, 7649546, 9104431, 10208479, 10978268, 17765246, 20145306, 21310417, 32770674, 34037665, 35052492, 35626767) and is highly recurrent in the Northern Italian population (PMID: 10978268). This variant has been identified in 13/249796 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Asp221Asn and p.Asp221Tyr, are considered to be disease-causing (ClinVar variation ID: 226331 and 251356), suggesting that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. - |
not provided Pathogenic:4Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 21, 2019 | This variant has been reported in individuals with familial hypercholesterolemia (PMID: 25461735 (2015), 20145306 (2010), 15241806 (2004), 11196104 (2000)). Assessment of experimental analysis yielded damaging results regarding the impact of this variant on protein function (PMID: 25647241 (2015), 1301956 (1992)). Therefore, we predict that this variant is pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 03, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Published in vitro over-expression and complementation studies suggest D221G is disruptive to LDLR activity (Thormaehlen et al., 2015); A different missense change at this residue (p.(D221N)) has been reported as pathogenic/likely pathogenic in association with FH at GeneDx and by other clinical laboratories (ClinVar Variant ID# 226331; ClinVar); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.D200G and FH Padua and FH Padova 1; This variant is associated with the following publications: (PMID: 15523646, 25487149, 1301956, 24529145, 11196104, 15241806, 25461735, 7649546, 9259195, 10206683, 11506462, 17142622, 17347910, 9104431, 10208479, 10978268, 32041611, 34182004, 33087929, 32977124, 28126585, 33740630, 34037665, 31447099, 32770674, 35177841, 34456049, 30710474, 35753512, 35971028, 9974426, 11939787, 25647241, 7682459, 28965616, 33303402, 35339733, 33955087, 35913489, 23375686) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jul 13, 2022 | - - |
| not provided, no classification provided | in vitro | Dept. of Genetics and Pharmacogenomics, Merck Research Labs | - | - - |
Homozygous familial hypercholesterolemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 03, 2019 | The p.Asp221Gly variant in LDLR has been reported in >75 individuals with familial hypercholesterolemia (FH), including in 4 homozygotes who presented with more severe disease (Hobbs 1992, Chmara 2010, Bertolini 2013). However, not all individuals carrying this variant presented with high cholesterol levels (Bertolini 2013, Thormaehlen 2015). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 183092) and has been identified in 13/111132 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs373822756). Please note that this frequency is low enough to be consistent with the frequency of FH in the general population. In vitro functional studies provide some evidence that the p.Asp221Gly variant may impact protein function (Thormaehlen 2015). In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon presence in affected individuals, low frequency in the general population, computational and functional evidence. The ACMG/AMP Criteria applied: PS4, PM3_Strong, PP3, PS3_Supporting. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 24, 2022 | The p.D221G pathogenic mutation (also known as c.662A>G), located in coding exon 4 of the LDLR gene, results from an A to G substitution at nucleotide position 662. The aspartic acid at codon 221 is replaced by glycine, an amino acid with similar properties. This mutation (referred to as D200G) was originally described in the compound heterozygous state in an Italian American with familial hypercholesterolemia (FH) in conjunction with another pathogenic allele. This patient's LDLR receptor activity was less than 2% of wild-type activity (Hobbs HH et al. Hum Mutat. 1992;1(6):445-66). In addition, this variant was further observed in 79 families and 165 individuals with clinically diagnosed heterozygous FH, which accounted for approximately 7.5% of unrelated individuals in the study (Bertolini S et al. Atherosclerosis. 2013; 227(2):342-8), and has subsequently been detected in additional FH studies (Santos RD et al. J Clin Lipidol. 2017;11(1):160-166; Pirillo A et al. Atheroscler Suppl. 2017;29:17-24). In vitro studies indicate significantly reduced amount of mature protein remaining in the endoplasmic reticulum, and reduced LDLR activity compared to wild type (Li et al. Biochemistry. 2002;41(15):4921-8; Thormaehlen AS et al. PLoS Genet. 2015;11(2):e1004855). Other alterations in the same codon (e.g., p.D221N and p.D221Y) have also been associated with FH. 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
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.;H
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;.;.;.
Vest4
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