Submissions for variant NM_000527.5(LDLR):c.769C>T (p.Arg257Trp)

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237953	SCV000294964	likely benign	Familial hypercholesterolemia 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	RCV000237953	SCV000503232	likely benign	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 2 / in association with c.1765G>A, p.Asp589Asn / Software predictions: Benign
Invitae	RCV000775048	SCV000544695	likely benign	Familial hypercholesterolemia	2020-12-01	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237953	SCV000583738	pathogenic	Familial hypercholesterolemia 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000237953	SCV000588517	uncertain significance	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000237953	SCV000607499	uncertain significance	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Robarts Research Institute,Western University	RCV000237953	SCV000782953	uncertain significance	Familial hypercholesterolemia 1	2018-01-02	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000775048	SCV000909147	uncertain significance	Familial hypercholesterolemia	2020-08-25	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Arg236Trp in the mature protein) is located in the sixth LDLR type A repeat in the ligand binding domain of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have demonstrated that the variant protein shows normal LDLR expression at the cell surface and normal LDL binding and uptake activity (PMID: 25545329). This variant has been reported in many individuals affected with familial hypercholesterolemia in Brazil, China, Germany, Korea and the Netherlands (PMID: 11462246, 11933210, 16250003, 20538126, 22353362, 25461735, 25962062, 26343872, 32759540). In two Chinese brothers with severe hypercholesterolemia, this variant co-occurred with two other heterozygous variants in LDLR (p.Gln191* and p.Asp589Asn) (PMID: 29365890). This variant and p.Asp589Asn have been reported to occur on the same allele (PMID: 16250003, 18325082). This variant has been identified in 26/282894 chromosomes (20/19954 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Functional studies and relatively high allele frequency in the general population indicate that this variant is unlikely to cause disease. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute	RCV000845535	SCV000987649	uncertain significance	not provided		criteria provided, single submitter	clinical testing
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia	RCV000237953	SCV001432577	uncertain significance	Familial hypercholesterolemia 1	2019-03-03	criteria provided, single submitter	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000237953	SCV000606221	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research