chr19-11120425-C-A
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000558518.6(LDLR):c.2043C>A(p.Cys681Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,784 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: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
LDLR
ENST00000558518.6 stop_gained
ENST00000558518.6 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: -0.847
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 19-11120425-C-A is Pathogenic according to our data. Variant chr19-11120425-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120425-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.2043C>A | p.Cys681Ter | stop_gained | 14/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LDLR | ENST00000558518.6 | c.2043C>A | p.Cys681Ter | stop_gained | 14/18 | 1 | NM_000527.5 | ENSP00000454071 | P3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251278Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135852
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461784Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5AN XY: 727210
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:34
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:21
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This variant changes 1 nucleotide in exon 14 of the LDLR gene, creating a premature translation stop signal. This variant is also known as p.Cys660* in the mature protein. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant causes a significant decrease in LDLR expression and LDL uptake (PMID: 31578082). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 3025214, 11668627, 19319977, 21145767, 25461735, 28502510, 28761763, 28873201, 31578082, 34321884) and is considered to be a founder variant in the Lebanese population (PMID: 19319977). This variant has also been observed in both homozygous and compound heterozygous state with a known pathogenic LDLR variant in multiple individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 28761763, 31578082). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 19319977, 34321884). This variant has been identified in 2/251278 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 the available evidence, this variant is classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 14, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | May 04, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Sep 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hypercholesterolaemia, 1 (MIM#143890). (I) 0108 - This gene is associated with both recessive and dominant disease. Variants have been reported in heterozygous, compound heterozygous and homozygous state with the recessive disease being more severe (OMIM, PMID: 10978268). (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic, and observed in individuals with familial hypercholesterolaemia (Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in both heterozygous and homozygous state in individuals with familial hypercholesterolaemia. It is regarded as a founder variant within the Lebanese population (ClinVar). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 21, 2023 | Criteria applied: PVS1,PS4,PM2_SUP,PP1 - |
| 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 | research | Iberoamerican FH Network | Mar 01, 2016 | - - |
| Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Aug 21, 2023 | PVS1, PM2, PP5 - It's pathogenicity has already been established. ClinVar Variation ID 3699. - |
| Pathogenic, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
| Pathogenic, criteria provided, single submitter | research | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | Mar 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation | Nov 05, 2016 | - - |
| Pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 02, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1991 | - - |
| 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 = 31 (1 homozygote) , family members = 17 with co-segregation / FH-Libanon, < 2% LDLR Activity - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen | Aug 09, 2018 | The nucleotide substitution c.2043C> A leads to a premature termination of protein synthesis at position 681 and is described as "FH Lebanese allele" in the literature. The mutation leads to intracellular degradation of the LDL receptor and loss of function. The mutation described here has also been described in patients with hypercholesterolemia and is therefore classified as pathogenic. PMID: 1453433, 3025214 - |
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 08, 2024 | 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; Reported many times in the heterozygous, compound heterozygous, and homozygous states in individuals with FH (PMID: 9664576, 9259195, 3025214, 10737984, 11668627, 12406975, 15200491, 28873201, 30179711); Considered a Lebanese founder mutation and may account for greater than 80% of FH cases in this population (PMID: 19319977); Published functional studies suggest a damaging effect on protein expression and binding (PMID: 31578082); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(C660X); This variant is associated with the following publications: (PMID: 31447099, 22487947, 25487149, 25525159, 3025214, 9259195, 9664576, 10737984, 11668627, 12406975, 15200491, 28873201, 30179711, 29407885, 34040191, 33303402, 34037665, 32041611, 33740630, 32770674, 33418990, 32231684, 35379577, 32009526, 33955087, 34321884, 15321837, 19319977, 37128917, 31578082) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 06, 2023 | This nonsense variant causes the premature termination of LDLR protein synthesis. The frequency of this variant in the general population, 0.000008 (2/251278 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported as a Lebanese founder mutation, but has also been identified in multiple other ethnic groups, in individuals and families with familial hypercholesterolemia (PMID: 28873201 (2017), 25461735 (2015), 22487947 (2012), 21145767 (2011), 19319977 (2009), 14974088 (2004), 11668627 (2001), 9664576 (1998), 3025214 (1987)). In a functional study, this variant was found to have a damaging effect on LDLR expression and binding (PMID: 31578082 (2019)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jul 13, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 04, 2023 | PP1, PS3, PS4_moderate, PVS1 - |
| Pathogenic, criteria provided, single submitter | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Familial hypercholesterolemia Pathogenic:5
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 17, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Jul 31, 2018 | The c.2043C>A (p.Cys681*) variant in the LDLR gene has been reported in multiple individual patients with familial Hypercholesterolemia and segregated in the families (PMID: 3025214, 1959928, 1453433, 12406975, 22487947). This variant is extremely rare in general population and is predicted to introduce a premature translation termination codon. Therefore, the c.2043C>A (p.Cys681*) variant in the LDLR gene is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 26, 2016 | Variant summary: The LDLR c.2043C>A (p.Cys681X) variant results in a premature termination codon, predicted to cause a truncated or absent LDLR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified in the pathogenic spectrum by our laboratory (e.g. p.Trp813X, p.Ser710fsX2 ). Mutation taster predicts a damaging outcome for this variant. This variant was found in 1/121136 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0025031). It was observed in several FH families and showed co-segregation with the disease indicating causality. Moreover, the variant was shown to result in lack of detectable high affinity binding and uptake of LDL, further supporting pathogenicity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 19, 2023 | This variant changes 1 nucleotide in exon 14 of the LDLR gene, creating a premature translation stop signal. This variant is also known as p.Cys660* in the mature protein. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant causes a significant decrease in LDLR expression and LDL uptake (PMID: 31578082). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 3025214, 11668627, 19319977, 21145767, 25461735, 28502510, 28761763, 28873201, 31578082, 34321884) and is considered to be a founder variant in the Lebanese population (PMID: 19319977). This variant has also been observed in both homozygous and compound heterozygous state with a known pathogenic LDLR variant in multiple individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 28761763, 31578082). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 19319977, 34321884). This variant has been identified in 2/251278 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 the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Cys681*) 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 present in population databases (rs121908031, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 1959928, 11668627, 19319977, 21145767, 22487947, 25461735). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys660*. ClinVar contains an entry for this variant (Variation ID: 3699). For these reasons, this variant has been classified as Pathogenic. - |
Homozygous familial hypercholesterolemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 22, 2021 | The p.Cys681X variant in LDLR has been reported in >80 individuals with hypercholesterolemia across several studies and segregated with disease in >10 affected relatives (Abifadel 2009, Banares 2017, Fahed 2011, Jannes 2015, Lehrman 1987, Tichy 2012, Vandrovcova 2013). This variant is considered to be a founder variant in the Lebanese population (Fahed 2016). This variant has also been reported in Clinvar (Variation ID 3699) and has been identified in 1/113666 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 681, 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 familial hypercholesterolemia (FH). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP criteria applied: PVS1, PS4, PM2, PP1_Strong. - |
See cases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Mar 04, 2021 | ACMG categories: PVS1,PM2,PP1,PP5 - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 29, 2022 | The c.2043C>A (p.C681*) alteration, located in exon 14 (coding exon 14) of the LDLR gene, consists of a C to A substitution at nucleotide position 2043. This changes the amino acid from a cysteine (C) to a stop codon at amino acid position 681. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration, also noted as p.C660X or the Lebanese allele, has been reported in individuals with familial hypercholesterolemia and a founder effect was proposed (Lehrman, 1987; Abifadel, 2009; Fahed, 2012). Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A;A;A;D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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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