ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1868TCA[1] (p.Ile624del)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237415 SCV000295730 likely 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 RCV000237415 SCV000503428 likely pathogenic Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 4, family members =7
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237415 SCV000583901 pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000237415 SCV000588619 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000237415 SCV000607651 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Invitae RCV001042592 SCV001206284 pathogenic Familial hypercholesterolemia 2023-08-16 criteria provided, single submitter clinical testing This variant, c.1871_1873del, results in the deletion of 1 amino acid(s) of the LDLR protein (p.Ile624del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 11668640, 15199436, 20145306, 23375686, 25378237, 25461735, 27824480, 28932795). ClinVar contains an entry for this variant (Variation ID: 252097). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects LDLR function (PMID: 25378237). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002411102 SCV002723510 pathogenic Cardiovascular phenotype 2022-03-30 criteria provided, single submitter clinical testing The c.1871_1873delTCA pathogenic mutation (also known as p.I624del) is located in coding exon 13 of the LDLR gene. This pathogenic mutation results from an in-frame TCA deletion at nucleotide positions 1871 to 1873. This results in the in-frame deletion of an isoleucine at codon 624. This variant (also known as p.I603del) has been detected in several unrelated individuals with familial hypercholesterolemia (FH), FH cohorts, and cohorts referred for FH genetic testing (Leren TP et al. Atherosclerosis, 2021 04;322:61-66; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909; Tada H et al. J Clin Lipidol 2020 Mar;14:346-351.e9; Gabová D et al. Physiol Res, 2017 03;66:75-84; Etxebarria A et al. Hum Mutat, 2015 Jan;36:129-41; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Chmara M et al. J Appl Genet, 2010;51:95-106). In a functional study, this variant was shown to result in significantly reduced LDLR expression, LDL binding, and LDL uptake compared to wild type (Etxebarria A et al. Hum Mutat, 2015 Jan;36:129-41). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics RCV000237415 SCV002783304 pathogenic Hypercholesterolemia, familial, 1 2021-09-24 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV003477856 SCV004219959 pathogenic not provided 2023-05-25 criteria provided, single submitter clinical testing The LDLR c.1871_1873del (p.Ile624del) variant has been reported in the published literature in multiple individuals with familial hypercholesterolemia (PMIDs: 11668640 (2001), 15199436 (2004), 19318025 (2009), 20145306 (2010), 23375686 (2013), 28932795 (2015), 25378237 (2015), 27824480 (2017), and 31491741 (2019)). In vitro functional studies indicated that this variant results in significantly reduced LDLR expression, LDL binding, and LDL uptake compared to wild type (PMID: 25378237 (2015)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237415 SCV000606548 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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