rs373371572
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS4PP1_StrongPM2PP3PP4
This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS4 - Variant meets PM2. Variant identified in 12 index cases.PP1_strong - 10 informative meioses identified by Laboratory of Genetics and Molecular Cardiology.PM2 - PopMax MAF = 0.00001548 (0.0015%) in European non-Finnish (gnomAD v2.1.1). PP3 - REVEL: 0,89. PP4 - Variant meets PM2. Variant identified in 12 index cases fulfilling validated clinical criteria for FH (6 cases with Simon-Broome or DLCN criteria from Ambry Genetics; 2 cases with Simon-Broome from Color laboratory; 3 cases with Simon-Broome criteria from Laboratory of Genetics and Molecular Cardiology; 1 case with Simon-Broome criteria from GeneDx). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023581/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1783C>T | p.Arg595Trp | missense_variant | 12/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1783C>T | p.Arg595Trp | missense_variant | 12/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152058Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251488Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135918
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461856Hom.: 0 Cov.: 34 AF XY: 0.0000151 AC XY: 11AN XY: 727230
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152058Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74270
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:11Uncertain:4
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 27, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Sep 07, 2020 | - - |
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 | - - |
Uncertain significance, 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 | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Dec 27, 2018 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Jun 09, 2021 | NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS4 - Variant meets PM2. Variant identified in 12 index cases. PP1_strong - 10 informative meioses identified by Laboratory of Genetics and Molecular Cardiology. PM2 - PopMax MAF = 0.00001548 (0.0015%) in European non-Finnish (gnomAD v2.1.1). PP3 - REVEL: 0,89. PP4 - Variant meets PM2. Variant identified in 12 index cases fulfilling validated clinical criteria for FH (6 cases with Simon-Broome or DLCN criteria from Ambry Genetics; 2 cases with Simon-Broome from Color laboratory; 3 cases with Simon-Broome criteria from Laboratory of Genetics and Molecular Cardiology; 1 case with Simon-Broome criteria from GeneDx). - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
Uncertain significance, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 09, 2024 | This missense variant (also known as p.Arg574Trp in the mature protein) replaces arginine with tryptophan at codon 595 in the fifth 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 20 individuals affected with familial hypercholesterolemia (PMID: 11737238, 16250003, 20538126, 25461735, 28502510, 32044282, 32331935, 34037665, 34176852; Color internal data), including three homozygous individuals with severe phenotype (PMID: 27784735). This variant has been identified in 2/282862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon (p.Arg595Leu and Arg595Gln) have been reported in individuals affected with familial hypercholesterolemia (ClinVar variation ID: 252029, 183126), suggesting that arginine at this position is a functionally and clinically important residue. Based on the available evidence, this variant is classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 09, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
Uncertain significance, criteria provided, single submitter | research | Iberoamerican FH Network | Mar 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 07, 2021 | - - |
Familial hypercholesterolemia Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | May 12, 2021 | The c.1783C>T (p.Arg595Trp) variant, also known as p.Arg574Trp in LDLR gene that encodes for low density lipoprotein receptor, has been identified in several unrelated individuals (>10) who fulfill the clinical criteria of familial hypercholesterolemia and segregated with disease in ten informative meioses (PMID:11737238, 16250003, 20538126, 25461735, 28502510). In-silico computational prediction tools suggest that the p.Arg595Trp variant may have deleterious effect on the protein function (REVEL score: 0.89). This variant is found to be rare (2/282862 chromosomes) in the general population database, gnomAD. This variant is interpreted as pathogenic by multiple submitters in the ClinVar database including the ClinGen expert panel (ClinVar ID: 161290). Another amino acid substitution at same position (p.Arg595Gln) has been classified as pathogenic by the ClinGen expert panel (ClinVar ID:183126). Therefore, the c.1783C>T (p.Arg595Trp) variant in LDLR gene is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Feb 14, 2022 | The c.1783C>T;p.(Arg595Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar: 161290; PMID: 11737238; 25461735; 27784735; 16250003; 20538126) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Ldl_recept_b) - PM1. The variant is present at low allele frequencies population databases (rs373371572 - gnomAD 0.0002631%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Pathogenic missense variant in this residue have been reported (ClinVar ID: 252029 - c.1784G>T;p.(Arg595Leu)) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 11737238; 16250003; 20538126) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 20, 2023 | This missense variant (also known as p.Arg574Trp in the mature protein) replaces arginine with tryptophan at codon 595 in the fifth 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 20 individuals affected with familial hypercholesterolemia (PMID: 11737238, 16250003, 20538126, 25461735, 28502510, 32044282, 32331935, 34037665, 34176852; Color internal data), including three homozygous individuals with severe phenotype (PMID: 27784735). This variant has been identified in 2/282862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon (p.Arg595Leu and Arg595Gln) have been reported in individuals affected with familial hypercholesterolemia (ClinVar variation ID: 252029, 183126), suggesting that arginine at this position is a functionally and clinically important residue. Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 595 of the LDLR protein (p.Arg595Trp). This variant is present in population databases (rs373371572, gnomAD 0.002%). This missense change has been observed in individuals with familial hypercholesterolaemia (PMID: 11737238, 16250003, 20538126, 25461735, 27784735). ClinVar contains an entry for this variant (Variation ID: 161290). 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.Arg595 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15256764, 15359125, 16250003, 18718593, 25437892, 25487149, 27497240, 28502510). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 30, 2019 | Variant summary: LDLR c.1783C>T (p.Arg595Trp) 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 4e-06 in 251488 control chromosomes. c.1783C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia in the homozygous and compound heterozygous state (Mozas_2004, Junyent_2010, Damgaard_2005, Chiou_2012, Pek_2018, Pirillo_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. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, three as VUS, six as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Mar 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 16, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 07, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported as a pathogenic variant by ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel (ClinVar Variant ID#171218; SCV001960931.1); Also known as p.(R574W); This variant is associated with the following publications: (PMID: 25637381, 28502510, 29172679, 28965616, 15823288, 16250003, 28502495, 30586733, 31491741, 31447099, 33740630, 34037665, 29353225, 32331935, 11737238, 15241806, 27578128, 30583242, 34906454, 34526433, 33994402, 34176852, 20538126, 25461735, 27784735) - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 19, 2024 | The c.1783C>T (p.R595W) alteration is located in coding exon 12 of the LDLR gene. This alteration results from a C to T substitution at nucleotide position 1783, causing the arginine (R) at amino acid position 595 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/282862) total alleles studied. The highest observed frequency was 0.002% (2/129168) of European (non-Finnish) alleles. This variant has been reported in several individuals with familial hypercholesterolemia (FH) from varying ethnic backgrounds (Descamps, 2001; Damgaard, 2005; Tejedor, 2005; Fouchier, 2005; Chiou, 2010; Jannes, 2015; Bañares, 2017; Pirillo, 2017; Pek, 2018). Another alteration at the same codon, p.R595Q (c.1784G>A), has also been detected in individuals with FH (Fouchier, 2005). This amino acid position is highly conserved in available vertebrate species. Functional studies of this variant demonstrated reduced binding capacity and receptor recycling (Guo, 2019). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Hypercholesterolemia Uncertain:1
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at