rs199774121
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000558518.6(LDLR):c.429C>A(p.Cys143Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,586 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
ENST00000558518.6 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.429C>A | p.Cys143Ter | 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.429C>A | p.Cys143Ter | stop_gained | 4/18 | 1 | NM_000527.5 | ENSP00000454071 | P3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251178Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135822
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461586Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6AN XY: 727118
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:9
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 | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Pathogenic, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Feb 18, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen | May 08, 2018 | This nonsense mutation leads to a complete loss of the receptor function. In addition, the variant was observed in multiple studies in patients with FH. In our case the mutation was observed in a patient with TC up to 550 mg/dl at the age of 35. PMID: 9212177, 25487149 - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genomics Laboratory, Stanford Medicine | Dec 31, 2020 | The p.Cys143* variant in the LDLR gene has been previously reported in at least 22 unrelated individuals with familial hypercholesterolemia (Descamps et al., 1997; Ekström et al., 1998; Lombardi et al., 1998; Jensen et al., 1999; Amsellem et al., 2002; van der Graaf et al., 2011; Natarajan et al., 2016), and one paper reported that it co-segregated with known or suspected FH in 71 relatives from 11 unrelated families (Descamps et al., 1997). This variant is also known as p.Cys122* in the literature. The p.Cys143* variant has been identified in 2/113,608 European (non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant leads to a premature stop codon in exon 4 of 18 coding exons, and is therefore predicted to undergo nonsensemediated decay resulting in a truncated or absent protein. Heterozygous loss of function is an established mechanism of disease for the LDLR gene. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Cys143* variant as pathogenic for autosomal dominant familial hypercholesterolemia based on the information above. [ACMG evidence codes used: PVS1; PS4; PM2] - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 05, 2024 | Criteria applied: PVS1,PS4,PM2_SUP - |
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 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 03, 2020 | This nonsense variant causes the premature termination of LDLR protein synthesis. It has been reported in individuals affected with familial hypercholesteremia in the published literature (PMID: 9767373 (1998), 9452078 (1998), 27831900 (2016), 21382890 (2011), 19318025 (2009)). Therefore, the variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Sep 08, 2022 | PVS1, PS4, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Nov 06, 2023 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 01, 2019 | The p.C143* pathogenic mutation (also known as c.429C>A), located in coding exon 4 of the LDLR gene, results from a C to A substitution at nucleotide position 429. This changes the amino acid from a cysteine to a stop codon within coding exon 4. This alteration has been reported in multiple subjects with familial hypercholesterolemia (FH) (Descamps O et al. Clin. Genet., 1997 May;51:303-8; Lombardi P et al. Hum. Mutat., 1998;Suppl 1:S172-4; Amsellem S et al. Hum. Genet., 2002 Dec;111:501-10; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73). 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. - |
Familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 17, 2023 | This sequence change creates a premature translational stop signal (p.Cys143*) 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 (rs199774121, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 9212177, 16542394, 21382890, 27831900). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys122*. ClinVar contains an entry for this variant (Variation ID: 226325). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at