Submissions for variant NM_000527.5(LDLR):c.1729T>C (p.Trp577Arg)

dbSNP: rs879255000

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237252	SCV000295618	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000237252	SCV000484705	likely pathogenic	Hypercholesterolemia, familial, 1		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	RCV000237252	SCV000503398	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 2 , family members = 3 with co-segregation / Other mutation at same codon/software prediction damaging
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791446	SCV000544666	pathogenic	Familial hypercholesterolemia	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 577 of the LDLR protein (p.Trp577Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11013454, 12436241, 15823276, 17347910, 18339137, 22528129, 27919346, 28126585). It is commonly reported in individuals of Turkey ancestry (PMID: 11013454, 12436241, 15823276, 17347910, 18339137, 22528129, 27919346, 28126585). This variant is also known as p.Trp556Arg. ClinVar contains an entry for this variant (Variation ID: 252001). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Trp577 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8697568, 9180246, 11810272, 25378237). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237252	SCV000583870	likely pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000237252	SCV000599386	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000237252	SCV002549731	likely pathogenic	Hypercholesterolemia, familial, 1	2022-01-05	criteria provided, single submitter	clinical testing	The LDLR p.Trp577Arg (originally p.Trp556Arg) missense variant is likely pathogenic for familial hypercholesterolaemia (FH). In silico algorithms (PolyPhen2, SIFT, MutationTaster) predict p.Trp577Arg to be pathogenic. It has previously been identified in multiple cohorts of FH patients worldwide and is absent from the gnomAD population database (~250,000 alleles). Other variants at the same position have been described as pathogenic (Trp577Cys, Trp577Gly, Trp577Ser).
Ambry Genetics	RCV002411087	SCV002716700	pathogenic	Cardiovascular phenotype	2021-07-06	criteria provided, single submitter	clinical testing	The p.W577R pathogenic mutation (also known as c.1729T>C), located in coding exon 12 of the LDLR gene, results from a T to C substitution at nucleotide position 1729. The tryptophan at codon 577 is replaced by arginine, an amino acid with dissimilar properties. This alteration, also referred to as p.W556R, has been reported in both the homozygous and heterozygous states in multiple Turkish families with familial hypercholesterolemia (FH) and was found to segregate with the disease (Gutierrez G et al. Hum. Mutat., 2000 Oct;16:374; Sözen MM et al. Atherosclerosis, 2005 May;180:63-71; Schmidt HH et al. Clin Transplant, 2008 Mar-Apr;22:180-4; Schaefer JR et al. Clin Res Cardiol Suppl, 2012 Jun;7:2-6; Taylan C et al. J Clin Lipidol 2016 Aug;10:1303-1310). This alteration was also described in association with FH in other populations (Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Amsellem S et al. Hum. Genet., 2002 Dec;111:501-10; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Widhalm K et al. J. Inherit. Metab. Dis., 2007 Apr;30:239-47; Fairoozy RH et al. Sci Rep, 2017 Dec;7:17087). Internal analysis has predicted that this alteration, located in the YWTD motif of LDLR class B report 5, disrupts the protein structure (Lo Surdo P et al. EMBO Rep., 2011 Dec;12:1300-5; Etxebarria A et al. Hum. Mutat., 2015 Jan;36:129-41). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237252	SCV000606500	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529326	SCV001742575	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001529326	SCV001917222	pathogenic	not provided		no assertion criteria provided	clinical testing