chr19-11110759-C-T
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS4PP1_StrongPM2PVS1PP4
This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.1048C>T(p.Arg350Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PVS1, PP4, PS4, PP1_Strong) 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:PM2: PopMax MAF = 0.00005 in East Asian population in gnomAD (gnomAD v2.1.1).PVS1: The variant causing a premature stop codon amino-terminal of amino acid 830 (NM_000527.5:p.Lys830).PP4: This variant meets PM2 and is identified in >1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded.PS4: Variant meets PM2 and is identified in 23 unrelated index cases fulfil clinical criteria for FH. Ten cases fulfil Simon Broome FH criteria (5 cases from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies , APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; 3 cases from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, PMID 22698793; 1 case from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge; 1 case from Division of Cardiology, Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan (PMID 20538126)). Thirteen cases fulfil DLCN criteria (10 cases from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA; 1 case each from Lipid Clinic, Fundación Jiménez Díaz, Madrid, Spain (PMID 19318025); Department of Genetics and Pathology, Pomeranian Medical Academy, Szczecin, Poland (PMID 9654205); GeneDx).PP1_Strong: Variant segregates with FH phenotype in 20 informative meiosis from at least 11 families. Fifteen affected relatives tested positive for the variant from at least 6 families from 4 different labs (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; GeneDx; Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA). Five unaffected relatives tested negative for the variant from 5 families (Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA). LINK:https://erepo.genome.network/evrepo/ui/classification/CA031387/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1048C>T | p.Arg350Ter | stop_gained | 7/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1048C>T | p.Arg350Ter | stop_gained | 7/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250716Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135606
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461026Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 726822
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74326
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:15
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation | Nov 05, 2016 | - - |
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 | Jun 05, 2008 | - - |
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 = 4 , family member = 3 with co-segregation / FH-Fossum - |
Pathogenic, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | research | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | Mar 01, 2016 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Mar 25, 2022 | The NM_000527.5 (LDLR):c.1048C>T(p.Arg350Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PVS1, PP4, PS4, PP1_Strong) 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: PM2: PopMax MAF = 0.00005 in East Asian population in gnomAD (gnomAD v2.1.1). PVS1: The variant causing a premature stop codon amino-terminal of amino acid 830 (NM_000527.5:p.Lys830). PP4: This variant meets PM2 and is identified in >1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PS4: Variant meets PM2 and is identified in 23 unrelated index cases fulfil clinical criteria for FH. Ten cases fulfil Simon Broome FH criteria (5 cases from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies , APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; 3 cases from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, PMID 22698793; 1 case from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge; 1 case from Division of Cardiology, Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan (PMID 20538126)). Thirteen cases fulfil DLCN criteria (10 cases from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA; 1 case each from Lipid Clinic, Fundación Jiménez Díaz, Madrid, Spain (PMID 19318025); Department of Genetics and Pathology, Pomeranian Medical Academy, Szczecin, Poland (PMID 9654205); GeneDx). PP1_Strong: Variant segregates with FH phenotype in 20 informative meiosis from at least 11 families. Fifteen affected relatives tested positive for the variant from at least 6 families from 4 different labs (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; GeneDx; Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA). Five unaffected relatives tested negative for the variant from 5 families (Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA). - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jan 20, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 24, 2023 | This variant (also known as p.Arg329X and FH-Fossum) changes 1 nucleotide in exon 7 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant. This variant been reported in numerous individuals affected with familial hypercholesterolemia (PMID: 7709162, 9039985, 21382890, 21310417, 22390909, 27680772, 28235710). It has also been reported in an individual affected with myocardial infarction (PMID: 25487149). This variant has been identified in 2/250716 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | Jan 26, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 01, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | research | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | 0/190 non-FH alleles; 0/100 healthy control individuals - |
Pathogenic, criteria provided, single submitter | clinical testing | North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust | Mar 10, 2022 | Criteria Codes: PP4 PM2 PP3 PS3_Supp PS4 - |
Pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 23, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as R329X and FH Fossum; This variant is associated with the following publications: (PMID: 7616128, 10208490, 21382890, 17765246, 25525159, 18263977, 25846081, 15256764, 17353666, 28502495, 19837725, 20145306, 20506408, 23054246, 25461735, 26875521, 22390909, 25487149, 7709162, 9654205, 19318025, 21310417, 23375686, 26415676, 27680772, 31727422, 28235710, 30592178, 32719484, 32522009, 33269076, 32770674, 32331935, 33740630, 33418990, 34037665, 33087929, 9039985, 26582918) - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Sep 15, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 05, 2019 | This variant causes the premature termination of LDLR protein synthesis. It has been reported in multiple individuals and families with familial hypercholesterolemia and/or early myocardial infarction in the published literature (PMIDs: 25487149 (2015), 25461735 (2015), 23375686 (2013), 21382890 (2011), 21310417 (2011), 20538126 (2010), and 7709162 (1994)). - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Feb 12, 2019 | - - |
Familial hypercholesterolemia Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 03, 2023 | This sequence change creates a premature translational stop signal (p.Arg350*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with familial hypercholesterolemia and myocardial infarction (PMID: 7709162, 9039985, 20809525, 21310417, 21382890, 22390909, 25487149). This variant is also known as Arg329*. ClinVar contains an entry for this variant (Variation ID: 226342). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 30, 2022 | This variant changes 1 nucleotide in exon 7 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as p.Arg329X and FH-Fossum in the literature. This variant been reported in numerous individuals affected with familial hypercholesterolemia (PMID: 7709162, 9039985, 21382890, 21310417, 22390909, 27680772, 28235710). It has also been reported in an individual affected with myocardial infarction (PMID: 25487149). This variant has been identified in 2/250716 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | research | Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 26, 2020 | Variant summary: LDLR c.1048C>T (p.Arg350X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 250716 control chromosomes (gnomAD). c.1048C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Bertolini_2013, Humphries_2006, Solberg_1994, van der Graaf_2011). These data indicate that the variant is very likely to be associated with disease. Ten ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Homozygous familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 05, 2019 | The p.Arg350X variant in LDLR (also described as p.Arg329X in the literature) has been reported in >15 individuals with hypercholesterolemia and segregated with disease in >15 affected relatives from 8 families (Day 1997, Humphries 2006, Kubalska 2008, Dušková 2011, van der Graaf 2011, Tichý 2012, Huijgen 2012, Radovica-Spalvina 2015, Do 2015, Fan 2015). This variant has also been identified in 1/111552 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs769737896) and in ClinVar (Variation ID: 226342). This nonsense variant leads to a premature termination codon at position 350, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in individuals with familial hypercholesterolemia (FH). In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner. The ACMG/AMP Criteria applied: PVS1; PS4; PP1_Strong; PM2. - |
Hypercholesterolemia, autosomal dominant, type B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop gained p.R350* in LDLR (NM_000527.5) has been reported in numerous individuals and families affected with familial hypercholesterolemia (Solberg K et al; Day IN et al; Huijgen R et al). The variant has been reported to ClinVar as Pathogenic. The variant is expected to result in an absent or disrupted protein product. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in LDLR are known to be pathogenic. For these reasons, this variant has been classified as Pathogenic. - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Jan 03, 2023 | ACMG categories: PVS1,PM2,PM5,PP3,PP5 - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 07, 2023 | The p.R350* pathogenic mutation (also known as c.1048C>T), located in coding exon 7 of the LDLR gene, results from a C to T substitution at nucleotide position 1048. This changes the amino acid from an arginine to a stop codon within coding exon 7. This mutation (also known as p.R329* / FH Fossum) has been detected in multiple individuals with familial hypercholesterolemia (FH) from a range of ethnic backgrounds, with at least one compound heterozygote and co-segregation also reported (Solberg K et al. Scand. J. Clin. Lab. Invest., 1994 Dec;54:605-9; Day IN et al. J. Med. Genet., 1997 Feb;34:111-6; Kubalska J et al. J. Appl. Genet., 2008;49:109-13; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Martin R et al. Atherosclerosis, 2016 11;254:8-13). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at