rs267607213
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.131G>A(p.Trp44Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,622 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: 0.0000034 ( 0 hom. )
Consequence
LDLR
NM_000527.5 stop_gained
NM_000527.5 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 9.48
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 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 19-11100286-G-A is Pathogenic according to our data. Variant chr19-11100286-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11100286-G-A is described in Lovd as [Pathogenic]. Variant chr19-11100286-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.131G>A | p.Trp44Ter | stop_gained | 2/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LDLR | ENST00000558518.6 | c.131G>A | p.Trp44Ter | stop_gained | 2/18 | 1 | NM_000527.5 | ENSP00000454071 | P3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461622Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727096
GnomAD4 exome
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5
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1461622
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31
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5
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727096
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GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:25
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:16
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 10, 2023 | This variant (also known as W23X in the mature protein and as FH Cincinnati-5) changes a single nucleotide in exon 2 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 has been reported in over 60 individuals affected with familial hypercholesterolemia (PMID: 1301956, 11668627, 16542394, 20145306, 20506408, 21382890, 22390909, 22698793). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 31048103). 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, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Jul 22, 2008 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 05, 1986 | - - |
| Pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | Jan 23, 2019 | - - |
| Likely pathogenic, criteria provided, single submitter | research | Institute for Integrative and Experimental Genomics, University of Luebeck | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Nov 24, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Sep 19, 2017 | This c.131G>A (p.Trp44*) variant in the LDLR gene is predicted to is predicted to introduce a premature translation termination codon. This variant has been reported in multiple patients with familial hypercholesterolemia (PMID: 1301956, 8850176). The c.131G>A (p.Trp44*) variant in the LDLR gene is classified as pathogenic. - |
| 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 | ACMG Guidelines: Pathogenic (ii) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 28, 2022 | - - |
| Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
| 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 = 10 , family members = 2 with co-segregation / FH-Cincinnati-5, 2 to 5% LDLR activity - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 30, 2023 | This sequence change creates a premature termination codon at position 44 in exon 2 (of 18) of LDLR, p.(Trp44*), also known as p.Trp23* and FH Cincinnati-5. It is expected to result in nonsense mediated decay, and loss of function is a well-established mechanism of disease for this gene (ClinGen). The variant is absent in a large population cohort (gnomAD v2.1 and v3.1). The variant is a recurrent mutation that has been identified in individuals with either homozygous or heterozygous familial hypercholesterolaemia, and segregates with disease in multiple families. Additionally, loss of LDL receptor activity has been identified in patient fibroblasts from an individual with this variant (PMID: 8850176, 1301956). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PP1_Strong, PM2_Supporting, PP4. - |
not provided Pathogenic:4
| Pathogenic, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Aug 16, 2016 | The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of four genes associated with familial hypercholesterolemia: LDLR, APOB, PCSK9 and LDLRAP1. Results showed that the following variant was identified (see report below): p.Trp44* (c.131G>A) in the LDLR gene (NM_000527.4) The lab classifies this variant as pathogenic. Given sufficient case data and the loss of function nature of this variant we consider this variant pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least nine unrelated cases of FH (not including this patient's family). This amounts to strong case data. Some of these individuals are reported as p.W23X in the literature due to alternate transcript terminology. See PMIDs: 1301956, 22390909, 21382890, 11668627, 22698793, 20145306, 16542394, 20506408). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 05, 2021 | PVS1, PS4, PM2, PS3_moderate, PM3_supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 20, 2020 | Not observed in large population cohorts (Lek et al., 2016); 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; Published functional studies demonstrate a damaging effect as this variant results in a null allele (Hobbs et al., 1992); Reported in ClinVar (ClinVar Variant ID# 3741; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 32665702, 32331935, 32719484, 32041611, 31447099, 31048103, 22390909, 26036859, 12417285, 9157944, 8645371, 8850176, 1301956, 25525159) - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Familial hypercholesterolemia Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 28, 2021 | Variant summary: LDLR c.131G>A (p.Trp44X) 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 was absent in 251254 control chromosomes. In a cross sectional ascertainment, c.131G>A has been widely reported in the literature in individuals affected with Familial Hypercholesterolemia (example, Hobbs_1992, Huijgen_2012, Luirink_2019, Dron_2020). These data indicate that the variant is likely to be associated with disease. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as 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 | Nov 09, 2023 | This sequence change creates a premature translational stop signal (p.Trp44*) 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 individual(s) with hypercholesterolemia (PMID: 1301956, 11668627, 16542394, 20145306, 20506408, 21382890, 22390909, 22698793). ClinVar contains an entry for this variant (Variation ID: 3741). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 01, 2023 | This variant (also known as W23X in the mature protein and as FH Cincinnati-5) changes a single nucleotide in exon 2 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 has been reported in over 60 individuals affected with familial hypercholesterolemia (PMID: 1301956, 11668627, 16542394, 20145306, 20506408, 21382890, 22390909, 22698793). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 31048103). 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. - |
Homozygous familial hypercholesterolemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 23, 2015 | The p.Trp44X variant in LDLR has been reported in a large number (>500) of indiv iduals with hypercholesterolemia (Hobbs 1992, Huijgen 2010, Chmara 2010, Duskova 2011, Fouchier 2015). It was absent from large population studies. This nonsens e variant leads to a premature termination codon at position 44, which is predic ted to lead to a truncated or absent protein. Heterozygous loss of LDLR function is an established disease mechanism in familial hypercholesterolemia. In summar y, this variant meets our criteria to be classified as pathogenic for hyperchole sterolemia in an autosomal dominant manner (http://www.partners.org/personalized medicince/LMM) based upon the predicted impact to the protein, its presence in a large number of affected individuals, and absence from controls. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 17, 2022 | The p.W44* pathogenic mutation (also known as c.131G>A), located in coding exon 2 of the LDLR gene, results from a G to A substitution at nucleotide position 131. This changes the amino acid from a tryptophan to a stop codon within coding exon 2. This mutation has been reported in multiple unrelated individuals with familial hypercholesterolemia (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Brusgaard K et al. Clin. Genet., 2006 Mar;69:277-83; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73; Wang J et al. Hum. Mutat., 2001 Oct;18:359; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8). 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
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;A;A;A;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
DS_DG_spliceai
Position offset: -3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at