rs752596535
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.501C>A(p.Cys167*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,652 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
LDLR
NM_000527.5 stop_gained
NM_000527.5 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: -0.555
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-11105407-C-A is Pathogenic according to our data. Variant chr19-11105407-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105407-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.501C>A | p.Cys167* | stop_gained | 4/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LDLR | ENST00000558518.6 | c.501C>A | p.Cys167* | stop_gained | 4/18 | 1 | NM_000527.5 | ENSP00000454071.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461652Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727122
GnomAD4 exome
AF:
AC:
2
AN:
1461652
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
727122
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:23
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:12
| 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 | 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, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
| Pathogenic, criteria provided, single submitter | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | May 11, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 08, 2022 | - - |
| Pathogenic, criteria provided, single submitter | research | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | Mar 01, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Apr 17, 2009 | - - |
| Pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 14, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Mar 06, 2024 | The c.501C>A (p.Cys167*) variant in the LDLR gene, that encodes for low density lipoprotein receptor, introduces a premature translation termination codon, resulting in an absent or disrupted protein product. The variant has been reported in several unrelated individuals (>10) affected with familial hypercholesterolemia (FH) (PMID: 10208479, 17539906, 21382890, 22698793, 26892515, 27680772, 34511120). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 33740630, 15321837, 20809525, 28645073). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID: 8828982, 22390909) and by several ClinVar submitters (ClinVar ID: 251274). This variant is found to be absent in the general population database, gnomAD and interpreted as pathogenic by multiple submitters in ClinVar (ClinVar ID: 200918). Therefore, the c.501C>A (p.Cys167*) variant in the LDLR gene is classified as pathogenic. - |
Familial hypercholesterolemia Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 20, 2023 | This sequence change creates a premature translational stop signal (p.Cys167*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 7616128, 10208479, 12406975, 21382890, 22698793, 26892515, 27765764). This variant is also known as Cys146X. ClinVar contains an entry for this variant (Variation ID: 200918). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 20, 2016 | Variant summary: The LDLR c.501C>A (p.Cys167X) variant, alternatively also known as C146X, results in a premature termination codon, predicted to cause a truncated or absent LDLR protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If NMD is escaped, this variant is expected truncate LDLR class A and B repeats, cysteine-rich domain, EGF-like calcium-binding domain, and EGF-like domain (InterPro). Truncations downstream of this position have been classified as pathogenic by our laboratory and others (e.g. p.Cys143X, p.Cys276X, p.Arg350X, etc.). This variant is absent in 121248 control chromosomes. In literature, this variant is reported as pathogenic variant and is found in many FH patients. The variant is particularly a frequent mutation in Dutch FH patients. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 13, 2020 | This variant changes 1 nucleotide in exon 4 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 studies have not been reported for this variant. This variant has been reported in more than 15 individuals affected with familial hypercholesterolemia (PMID: 7616128, 10208479, 17539906, 21382890, 22698793, 23833242, 26892515, 27765764). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Aug 29, 2022 | The c.501C>A (p.Cys167*) variant in the LDLR gene, that encodes for low density lipoprotein receptor, introduces a premature translation termination codon, resulting in an absent or disrupted protein product. The variant has been reported in several unrelated individuals (>10) affected with familial hypercholesterolemia (FH) (PMID: 10208479, 17539906, 21382890, 22698793, 26892515, 27680772, 34511120). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 33740630, 15321837, 20809525, 28645073). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID: 8828982, 22390909) and by several ClinVar submitters (ClinVar ID: 251274). This variant is found to be absent in the general population database, gnomAD and interpreted as pathogenic by multiple submitters in ClinVar (ClinVar ID: 200918). Therefore, the c.501C>A (p.Cys167*) variant in the LDLR gene is classified as pathogenic. - |
not provided Pathogenic:3
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | - | Genetic testing: The patient had genetic testing for the familial LDLR mutation that was first identified in her brother, p.167*. at Ambry Genetics. Results reported on July 5, 2016 showed that the following variant was identified. Ambry classifies this variant as pathogenic. Given the loss of function nature of this variant and sufficient case data in other individuals we consider this variant pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant was previously identified in an affected family member of a patient. An individual with a missense variant at this codon is reported in Clinvar. Lombardi P et al. J. Lipid Res. 1995;36(4):860-7 reported this variant as it's other name (p.Cys146*) and Heath KE et al. Atherosclerosis 1999;143(1):41-54 reported this variant in a 27 Y male with FH. This variant is not reported in ExAC. - |
Homozygous familial hypercholesterolemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 09, 2018 | The p.Cys167X variant in LDLR (also described as p.Cys146X in the literature) ha s been reported in the heterozygous state in >10 individuals with familial hyper cholesterolemia (FH), segregated with disease in one affected relative from one family (Lombardi 1995, Heath 1999, Fouchier 2001, Bodamer 2002, van der Graaf 20 11, Tichy 2012, Sharifi 2016) and was absent from large population studies. Addi tionally, this variant has been reported by other clinical laboratories in ClinV ar (Variation ID: 200918). This nonsense variant leads to a premature terminatio n codon at position 167, which is predicted to lead to a truncated or absent pro tein. Heterozygous loss of function of the LDLR gene is an established disease m echanism in FH. In summary, this variant meets our criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner bas ed upon predicted impact to the protein, presence in multiple affected individua ls and absence in the general population. ACMG/AMP Criteria applied (Richards 20 15): PVS1, PS4_Moderate, PM2. - |
See cases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Nov 14, 2022 | ACMG categories: PVS1,PM2,PP3,PP5 - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 06, 2021 | The p.C167* pathogenic mutation (also known as c.501C>A), located in coding exon 4 of the LDLR gene, results from a C to A substitution at nucleotide position 501. This changes the amino acid from a cysteine to a stop codon within coding exon 4. This mutation (referred to as p.C146X) has been described in multiple unrelated individuals with familial hypercholesterolemia (Lombardi P et al. J. Lipid Res. 1995;36(4):860-7; Heath KE et al. Atherosclerosis 1999;143(1):41-54; Rieck L et al. Clin Genet. 2020 11;98(5):457-467). In in vitro functional studies, this variant showed significantly reduced or absent protein expression and function compared to wild type (Hu H et al. Lipids Health Dis. 2021 Sep;20(1):101). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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