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

gnomAD frequency: 0.00010  dbSNP: rs200990725

Total submissions: 18

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000775048	SCV000544695	likely benign	Familial hypercholesterolemia	2025-01-28	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	2024-07-31	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 257 in the sixth LDLR type A repeat in the ligand binding domain of the LDLR protein. This variant is also known as p.Arg236Trp in the mature protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. 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, 38003014). In two Chinese siblings with severe hypercholesterolemia, this variant co-occurred with two other heterozygous variants in LDLR (p.Gln191* and p.Asp589Asn) (PMID: 29399563). 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	2024-07-08	criteria provided, single submitter	clinical testing	Observed in multiple unrelated patients from different ethnic backgrounds with familial hypercholesterolemia (FH) in the published literature (PMID: 26690388, 32759540, 11462246, 11933210, 16250003, 19318025, 20538126, 25962062, 25461735, 26343872, 26875521, 29353225, 30526649, 30293936, 30592178, 34573395); 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; these variants are suspected to be linked on the same allele (PMID: 16250003, 20538126, 25962062, 29399563, 30795984, 33994402); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R236W); 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, 16250003, 32041611, 32719484, 35538921, 30400955, 29399563, 35999587, 18325082, 35560019, 26690388, 32759540, 34573395, 30795984, 33994402, 34456200)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000845535	SCV002047051	uncertain significance	not provided	2023-10-19	criteria provided, single submitter	clinical testing	The LDLR c.769C>T (p.Arg257Trp) variant (also known as R257W and R236W) has been reported in the published literature in multiple individuals affected with hypercholesterolemia (PMIDs: 11462246 (2001), 11933210 (2002), 19318025 (2009), 22353362 (2012), 25461735 (2015), 29353225 (2018), 29399563 (2018), 30293936 (2018), 31345425 (2019), 32759540 (2020), 34573395 (2021), 35137788 (2022)). In addition, this variant is often seen together with another LDLR variant, c.1765G>A (p.Asp589Asn). When this complex allele occurs in the homozygous phase or in trans with other deleterious LDLR variants, c.986G>A (p.Cys329Tyr) or c.1754T>A (p.Ile585Asn), the phenotype appears more severe and is suggestive of homozygous hypercholesterolemia (HoFH) (PMIDs: 30795984 (2019), 25962062 (2015), 20538126 (2010)). A functional study, however, indicated that the c.769C>T (p.Arg257Trp) variant showed normal levels of LDLR protein expression as well as normal LDL binding and uptake activity (PMID: 25545329 (2015)). Another report described the variant to retain 85% activity (PMID: 27206935 (2016)) and further research is necessary. The frequency of this variant in the general population, 0.0012 (18/14424 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Ambry Genetics	RCV002401930	SCV002669523	uncertain significance	Cardiovascular phenotype	2024-04-11	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 (also referred to as p.R236W) has been previously described in several individuals with familial hypercholesterolemia (FH) from various ethnic backgrounds, often along with the LDLR p.D589N variant (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. Based on the available evidence, the clinical significance of this variant remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001800605	SCV003844390	likely benign	not specified	2024-06-18	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 estimated 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 without strong evidence of causality (e.g. Luirink_2019, Huang_2022, Kim_2022). 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). The following publications have been ascertained in the context of this evaluation (PMID: 25545329, 30795984, 34456200, 33994402). ClinVar contains an entry for this variant (Variation ID: 251446). Based on the evidence outlined above, the variant was classified as likely benign.
All of Us Research Program, National Institutes of Health	RCV000237953	SCV004820210	uncertain significance	Hypercholesterolemia, familial, 1	2024-08-13	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: 29399563). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000845535	SCV005875779	uncertain significance	not provided	2024-09-13	criteria provided, single submitter	clinical testing	The LDLR c.769C>T; p.Arg257Trp variant (rs200990725, ClinVar Variation ID 251446) is reported along with another LDLR variant, c.1765G>A; p.Asp589Asn, as linked variants in individuals affected with hypercholesterolemia (Gratton 2023, Huang 2022, Olfson 2015). Affected individuals had an additional variant in trans (on opposite chromosome) to these linked LDLR variants. LDLR Arg257Trp is found predominantly in the East Asian population with an allele frequency of 0.1% (20/19954 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.648). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Gratton J et al. Prevalence of FH-Causing Variants and Impact on LDL-C Concentration in European, South Asian, and African Ancestry Groups of the UK Biobank-Brief Report. Arterioscler Thromb Vasc Biol. 2023 Sep. PMID: 37409534. Huang CC et al. Genetic Analysis in a Taiwanese Cohort of 750 Index Patients with Clinically Diagnosed Familial Hypercholesterolemia. J Atheroscler Thromb. 2022 May 1. PMID: 33994402. Olfson E et al. Identification of Medically Actionable Secondary Findings in the 1000 Genomes. PLoS One. 2015 PMID: 26332594.
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