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

Total submissions: 15

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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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	2020-10-08	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 Health, Inc	RCV000588105	SCV000909180	likely pathogenic	Familial hypercholesterolemia	2019-03-22	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	2020-09-07	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
Institute of Human Genetics, Klinikum rechts der Isar	RCV000237585	SCV001149823	likely pathogenic	Familial hypercholesterolemia 1	2018-12-27	no assertion criteria provided	clinical testing