ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237585 SCV000295653 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237585 SCV000494601 pathogenic Familial hypercholesterolemia 1 2017-03-30 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 RCV000237585 SCV000503414 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH/software prediction damaging
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000237585 SCV000588606 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000237585 SCV000607640 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Athena Diagnostics Inc RCV000518174 SCV000614004 likely pathogenic not provided 2017-06-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588105 SCV000697210 pathogenic Familial hypercholesterolemia 2019-09-30 criteria provided, single submitter clinical testing Variant summary: LDLR c.1783C>T (p.Arg595Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251488 control chromosomes. c.1783C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia in the homozygous and compound heterozygous state (Mozas_2004, Junyent_2010, Damgaard_2005, Chiou_2012, Pek_2018, Pirillo_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, three as VUS, six as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Iberoamerican FH Network RCV000237585 SCV000748099 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV000588105 SCV000752411 pathogenic Familial hypercholesterolemia 2019-10-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 595 of the LDLR protein (p.Arg595Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs373371572, ExAC 0.001%). This variant has been observed in several individuals affected with familial hypercholesterolaemia (PMID: 11737238, 25461735, 27784735, 16250003, 20538126). ClinVar contains an entry for this variant (Variation ID: 161290). This variant disrupts the p.Arg595 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 15359125, 15256764, 16250003, 18718593, 25437892, 25487149, 27497240, 28502510), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Color RCV000588105 SCV000909180 likely pathogenic Familial hypercholesterolemia 2019-03-22 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000237585 SCV001149823 likely pathogenic Familial hypercholesterolemia 1 2018-12-27 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000518174 SCV001433287 likely pathogenic not provided 2020-03-16 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000237585 SCV001440210 uncertain significance Familial hypercholesterolemia 1 2019-01-01 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148597 SCV000190312 uncertain significance Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237585 SCV000606512 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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