rs570942190
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Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Very_Strong
The ENST00000558518.6(LDLR):c.1246C>T(p.Arg416Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,778 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. R416L) has been classified as Likely pathogenic.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 29)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
LDLR
ENST00000558518.6 missense
ENST00000558518.6 missense
Scores
10
5
4
Clinical Significance
Conservation
PhyloP100: 0.809
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 ENST00000558518.6 (LDLR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 9 uncertain in ENST00000558518.6
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-11113338-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.978
PP5
Variant 19-11113337-C-T is Pathogenic according to our data. Variant chr19-11113337-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113337-C-T is described in Lovd as [Pathogenic]. Variant chr19-11113337-C-T is described in Lovd as [Likely_pathogenic]. Variant chr19-11113337-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.1246C>T | p.Arg416Trp | missense_variant | 9/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LDLR | ENST00000558518.6 | c.1246C>T | p.Arg416Trp | missense_variant | 9/18 | 1 | NM_000527.5 | ENSP00000454071 | P3 |
Frequencies
GnomAD3 genomes 0.0000132 AC: 2AN: 152056Hom.: 0 Cov.: 29
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251158Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135870
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461604Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727120
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GnomAD4 genome 0.0000131 AC: 2AN: 152174Hom.: 0 Cov.: 29 AF XY: 0.0000134 AC XY: 1AN XY: 74396
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:24Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:15
| Likely pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 07, 2024 | Criteria applied: PS4,PM5_STR,PM2,PP3 - |
| 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 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 18, 2023 | This missense variant (also known as p.Arg395Trp in the mature protein) replaces arginine with tryptophan at codon 416 in the LDLR type B repeat of the EGF precursor homology 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 that this variant decreases LDLR cell surface expression and LDL uptake, and causes defective LDLR recycling due to protein degradation in lysosomes (PMID 25378237). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 9104431, 9259195, 11196104, 11668640, 14974088, 17539906, 18700895, 20538126, 20663204, 21310417, 21376320, 23375686, 25378237, 25921077, 25962062, 26892515, 27784735, 28104544, 32423031, 33740630, 33955087, 33994402, 34037665, 34407635, 34834584, 36499307). It has been shown that this variant segregates with hypercholesterolemia in multiple Norwegian families (PMID: 9104431). This variant has been identified in 6/251158 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg416Gln, is considered to be disease-causing (ClinVar variation ID: 251752), suggesting that arginine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PS3+PS4+PP4 - |
| Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
| Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
| Pathogenic, criteria provided, single submitter | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | Mar 13, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 11, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | May 22, 2012 | - - |
| Likely pathogenic, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The LDLR c.1246C>T (p.Arg416Trp) variant, also referred to as p.Arg395Trp, has been identified in a heterozygous state in 33 individuals of different ethnicities with either definite or possible familial hypercholesterolemia (FH) (Day et al. 1997; Leren et al. 1997; Wang et al. 2001; Garcia-Garcia et al. 2001; Dedoussis et al. 2004; Tichy et al. 2012; Bertolini et al. 2013). An additional study detected either the p.Arg416Trp variant or one of two other common variants in the LDLR gene in 186 of 1,945 Czech individuals with a probable or definite diagnosis of FH (Goldmann et al. 2010). Leren et al. (1997) also note that the p.Arg416Trp variant segregated with disease in family members of the nine unrelated individuals in their study. The variant was absent from 60 total control individuals and is reported at a frequency of 0.00002 in the Total population of the Exome Aggregation Consortium. Functional studies indicated that with the p.Arg416Trp variant, LDLR expression on the cell surface and LDL uptake efficiency were decreased when compared to wildtype, suggesting defective receptor recycling (Etxebarria et al. 2015). Based on the evidence, the p.Arg416Trp variant is classified as pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| 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 | 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 | - - |
not provided Pathogenic:4Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jul 13, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 21, 2023 | The frequency of this variant in the general population, 0.000098 (3/30616 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with familial or isolated hypercholesterolemia (PMIDs: 36901902 (2023), 34456049 (2022), 35913489 (2022), 35339733 (2022), 33955087 (2021), 34407635 (2021), 33303402 (2021), 33994402 (2021) 33418990 (2021), 34037665 (2021), 33740630 (2021), 32423031 (2020), 31447099 (2019), 30592178 (2019), 31345425 (2019), 29531935 (2018), 28104544 (2017)). Functional studies show the variant impacts LDLR expression and binding (PMIDs: 25378237 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. - |
| not provided, no classification provided | in vitro | Dept. of Genetics and Pharmacogenomics, Merck Research Labs | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 29, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest defective receptor recycling, membrane localization, binding activity, and LDL particle uptake (Etxebarria et al., 2015; Thormaehlen et al., 2015; Galicia-Garcia et al., 2020; Duskova et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as R395W; This variant is associated with the following publications: (PMID: 9259195, 17539906, 18700895, 25921077, 26892515, 34407635, 32423031, 35339733, 33391333, 33133164, 23375686, 25487149, 25647241, 9104431, 11196104, 11668640, 14974088, 20045108, 20663204, 21310417, 28104544, 28965616, 30592178, 29531935, 31447099, 20538126, 32015373, 32629184, 32695144, 32041611, 33303402, 32331935, 33740630, 33418990, 34037665, 34456049, 35913489, 33955087, 33994402, 25378237) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 15, 2020 | PS4, PM1, PM2, PS3_Moderate, PP3 - |
Familial hypercholesterolemia Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 21, 2016 | Variant summary: The LDLR c.1246C>T (p.Arg416Trp) variant (alternatively also known as R395W) is located in the six-bladed beta-propeller, TolB-like domain of the protein (InterPro). 4/4 in silico tools predict a damaging outcome for this variant. Functional analyses conclude that this variant results in defective LDLR recycling (Etxebarria_2015). The variant is widely reported as a pathogenic variant in literature found across many countries (Schmidt_2000, Real_2003, Leren_2004, Charng_2006, Humphries_2006, Tichy_2012). Other missense changes at this codon, namely p.Arg416Leu, p.Arg416Pro and p.Arg416Gln have been associated with FH, supporting that the codon is likely to be a mutational hot-spot. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. This variant was found in 3/120616 control chromosomes at a frequency of 0.0000249, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0010005). The heterozygotes in ExAC are likely to represent as subclinical cases or reduced penetrance as it is recurrently found mutation in FH patients. Taken together, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 09, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 416 of the LDLR protein (p.Arg416Trp). This variant is present in population databases (rs570942190, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9104431, 9259195, 11196104, 11668640, 14974088, 17539906, 18700895, 20538126, 20663204, 21310417, 21376320, 23375686, 25378237, 25921077, 25962062, 26892515). This variant is also known as p.Arg395Trp. ClinVar contains an entry for this variant (Variation ID: 183110). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 25378237, 25647241). This variant disrupts the p.Arg416 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 20045108, 20538126), 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 | Jul 27, 2023 | This missense variant (also known as p.Arg395Trp in the mature protein) replaces arginine with tryptophan at codon 416 in the LDLR type B repeat of the EGF precursor homology 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 that this variant decreases LDLR cell surface expression and LDL uptake, and causes defective LDLR recycling due to protein degradation in lysosomes (PMID 25378237). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 9104431, 9259195, 11196104, 11668640, 14974088, 17539906, 18700895, 20538126, 20663204, 21310417, 21376320, 23375686, 25378237, 25921077, 25962062, 26892515, 27784735, 28104544, 32423031, 33740630, 33955087, 33994402, 34037665, 34407635, 34834584, 36499307). It has been shown that this variant segregates with hypercholesterolemia in multiple Norwegian families (PMID: 9104431). This variant has been identified in 6/251158 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg416Gln, is considered to be disease-causing (ClinVar variation ID: 251752), suggesting that arginine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. - |
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.Arg416Trp variant in LDLR has been reported in >30 individuals with familial hypercholesterolemia (FH) and segregated with disease in 1 affected relative (Day 1997, Dušková 2011, Tichý 2012, Bertolini 2013, Do 2015, Etxebarria 2015, Han 2015, Sánchez-Hernández 2016, Sharifi 2016, Durst 2017). It has also been reported by other clinical laboratories in ClinVar (Variation ID: 183110) and been identified in 3/30782 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs570942190). This frequency is low enough to be consistent with the frequency of FH in the general population. Amino acid position 416 is a known mutation hotspot, with many other variants (p.Arg416Pro, p.Arg416Leu and p.Arg416Gln) reported in individuals with FH (Liguori 2001, Bertolini 2013, Chiou 2010, Thiart 1998, Huijgen 2012). Functional studies provide some evidence that the p.Arg416Trp variant may impact protein function (Etxebarria 2015). In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon presence in multiple affected individuals, low frequency in the general population, functional and computational evidence and its presence in a known mutational hotspot. The ACMG/AMP criteria applied: PS4, PM1, PM2, PS3_Moderate, PP3 (Richards 2015). - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 21, 2024 | The c.1246C>T (p.R416W) alteration is located in exon 9 (coding exon 9) of the LDLR gene. This alteration results from a C to T substitution at nucleotide position 1246, causing the arginine (R) at amino acid position 416 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.002% (6/251158) total alleles studied. The highest observed frequency was 0.01% (3/30616) of South Asian alleles. This alteration, also known as R395W, has been described in a number of hypercholesterolemic individuals worldwide, and has been reported to segregate with the disease in several families (Day, 1997; Leren, 1997; Schmidt, 2000; Weiss, 2000; Fouchier, 2001; García-García, 2001; Wang, 2001; Dedoussis, 2004; Chiou, 2010; Goldmann, 2010; Bertolini, 2013; Shin, 2015; Han, 2015; Sharifi, 2016). This amino acid position is well conserved in available vertebrate species. Functional studies have indicated this alteration would affect protein recycling, causing reduced LDLR membrane expression and thus reduced ligand uptake (Etxebarria, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
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AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
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
Uncertain
M;.;.;.;.;M
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
Uncertain
D;D;D;D;D;D
Polyphen
D;.;.;.;.;.
Vest4
MutPred
Loss of disorder (P = 0.0075);Loss of disorder (P = 0.0075);.;.;.;Loss of disorder (P = 0.0075);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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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