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

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237953	SCV000294964	likely benign	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	RCV000237953	SCV000503232	likely benign	Hypercholesterolemia, familial, 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	2023-12-30	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237953	SCV000583738	likely benign	Hypercholesterolemia, familial, 1	2024-01-31	criteria provided, single submitter	clinical testing	This missense variant LDLR:c.769C>T (also known as p.Arg236Trp in the mature protein), replaces a arginine with tryptophan at codon 257 of the LDLR protein (p.Arg257Trp). According to updated genomic data and to ClinGen FH VCEP criteria issued in 2022 (PMID: 34906454) for the validation of pathogenicity of LDLR variants, this variant may now be reclassified as “Likely Benign” from evidence as follows. It is located within a conserved (REVEL=0.648) functional domain (LDLR Class A6) involved in LDL binding with LDL receptors. Because this variant is observed with a frequency <0.02% in the general population (GnomAD= 0.0000985, no homozygotes) multiple reports classify this variant as VUS (PM2). However, despite apparent cosegregation in several independent FH families, it has been frequently observed in normolipidemic individuals (BS2) or in Cis with other proven pathogenic variants in FH patients (BP2). Finally, several independent level 1 in-vitro functional studies have shown consistently that this variant has a neutral effect on LDLR function (BS3).
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000237953	SCV000588517	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000237953	SCV000607499	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Robarts Research Institute, Western University	RCV000237953	SCV000782953	uncertain significance	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000775048	SCV000909147	uncertain significance	Familial hypercholesterolemia	2022-12-09	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 or suspected of having familial hypercholesterolemia in Brazil, China, Germany, Korea and the Netherlands (PMID: 11462246, 11933210, 16250003, 20538126, 22353362, 25461735, 25962062, 26343872, 32759540, 33994402, 34456200, 34573395, 35137788). 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	Hypercholesterolemia, familial, 1	2019-03-03	criteria provided, single submitter	research
GeneDx	RCV000845535	SCV002004038	uncertain significance	not provided	2021-06-28	criteria provided, single submitter	clinical testing	Observed in multiple unrelated patients from different ethnic backgrounds with familial hypercholesterolemia (FH) in the published literature (Nauck et al., 2001; Salazar et al., 2002; Fouchier et al., 2005; Alonso et al., 2009; Chiou et al., 2010; Han et al., 2015; Jannes et al., 2015; Shin et al., 2015; Tang et al., 2015; Hu et al., 2016; Pek et al., 2017; Cao et al., 2018; Martin Campos et al., 2018; Chan et al., 2019); Many individuals with p.R257W in the published literature harbor a second variant in LDLR (p.D589N) in cis, including two individuals homozygous for both variants (Han et al., 2015; Chiou et al., 2010); these variants are suspected to be linked on the same allele; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 251446; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30592178, 29083407, 29353225, 30526649, 30293936, 11462246, 20538126, 26332594, 11933210, 25461735, 25962062, 26343872, 19318025, 26875521, 22353362, 25545329, 27535533, 26582918, 26690388, 16250003, 32041611, 32719484)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800605	SCV002047051	uncertain significance	not specified	2021-05-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002401930	SCV002669523	uncertain significance	Cardiovascular phenotype	2022-06-27	criteria provided, single submitter	clinical testing	The p.R257W variant (also known as c.769C>T), located in coding exon 5 of the LDLR gene, results from a C to T substitution at nucleotide position 769. The arginine at codon 257 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been previously described in several individuals with familial hypercholesterolemia (FH) from various ethnic backgrounds, most often along with LDLR p.D589N (Nauck MS et al. Hum Mutat. 2001;18:165-6; Salazar LA et al. Hum Mutat. 2002;19:462-3; Fouchier SW et al. Hum Mutat. 2005;26:550-6; Chiou KR et al. Am J Cardiol. 2010;105:1752-8; Han SM et al. PLoS ONE. 2015;10:e0126706; Pek SLT et al. Atherosclerosis, 2018 Feb;269:106-116). In functional in vitro analyses, the p.R257W variant has demonstrated similar effects as the wild-type, including low-density lipoprotein receptor (LDLR) expression and the ability to bind and internalize LDL (Etxebarria A et al. Atherosclerosis. 2015;238:304-12). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001800605	SCV003844390	likely benign	not specified	2023-02-06	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.769C>T (p.Arg257Trp) 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 9.5e-05 in 251486 control chromosomes, predominantly at a frequency of 0.00098 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (9.5e-05 vs 0.0013), allowing no conclusion about variant significance. c.769C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia. These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Etxebarria_2015). Thirteen 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 (Pathogenic n=1, likely benign n=4, VUS n=8). Based on the evidence outlined above, the variant was classified as likely benign.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237953	SCV000606221	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000775048	SCV002086387	likely benign	Familial hypercholesterolemia	2020-10-08	no assertion criteria provided	clinical testing