ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.429C>A (p.Cys143Ter)

gnomAD frequency: 0.00001  dbSNP: rs199774121
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211567 SCV000294707 pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000211567 SCV000503157 pathogenic Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 7 , family members = 5 with co-segregation
Invitae RCV002229196 SCV000544658 pathogenic Familial hypercholesterolemia 2023-07-17 criteria provided, single submitter clinical testing 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.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211567 SCV000583677 pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
Fundacion Hipercolesterolemia Familiar RCV000211567 SCV000607456 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen RCV000211567 SCV000987026 pathogenic Hypercholesterolemia, familial, 1 2018-05-08 criteria provided, single submitter clinical testing 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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001800540 SCV002046188 pathogenic not provided 2020-12-03 criteria provided, single submitter clinical testing 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.
Ambry Genetics RCV002327075 SCV002630846 pathogenic Cardiovascular phenotype 2019-11-01 criteria provided, single submitter clinical testing 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV001800540 SCV004026159 pathogenic not provided 2022-09-08 criteria provided, single submitter clinical testing PVS1, PS4, PP3
Institute of Human Genetics, University of Leipzig Medical Center RCV000211567 SCV004032280 pathogenic Hypercholesterolemia, familial, 1 2024-03-05 criteria provided, single submitter clinical testing Criteria applied: PVS1,PS4,PM2_SUP
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211567 SCV000268564 pathogenic Hypercholesterolemia, familial, 1 2016-02-18 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000211567 SCV000606117 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research
Clinical Genomics Program, Stanford Medicine RCV000211567 SCV004100862 pathogenic Hypercholesterolemia, familial, 1 2020-12-31 no assertion criteria provided clinical testing 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 ( 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]

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