Submissions for variant NM_000527.5(LDLR):c.1246C>T (p.Arg416Trp)

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211633	SCV000295325	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Illumina Laboratory Services, Illumina	RCV000211633	SCV000410532	pathogenic	Hypercholesterolemia, familial, 1	2017-04-27	criteria provided, single submitter	clinical testing	The LDLR c.1246C>T (p.Arg416Trp) variant, also referred to as p.Arg395Trp, has been identified in a heterozygous state in 33 individuals of different ethnicities with either definite or possible familial hypercholesterolemia (FH) (Day et al. 1997; Leren et al. 1997; Wang et al. 2001; Garcia-Garcia et al. 2001; Dedoussis et al. 2004; Tichy et al. 2012; Bertolini et al. 2013). An additional study detected either the p.Arg416Trp variant or one of two other common variants in the LDLR gene in 186 of 1,945 Czech individuals with a probable or definite diagnosis of FH (Goldmann et al. 2010). Leren et al. (1997) also note that the p.Arg416Trp variant segregated with disease in family members of the nine unrelated individuals in their study. The variant was absent from 60 total control individuals and is reported at a frequency of 0.00002 in the Total population of the Exome Aggregation Consortium. Functional studies indicated that with the p.Arg416Trp variant, LDLR expression on the cell surface and LDL uptake efficiency were decreased when compared to wildtype, suggesting defective receptor recycling (Etxebarria et al. 2015). Based on the evidence, the p.Arg416Trp variant is classified as pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Robarts Research Institute, Western University	RCV000211633	SCV000484694	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	RCV000211633	SCV000503322	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 7 , family members = 3 with co-segregation / previously described in association with FH / Software predictions: Damaging
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000211633	SCV000540805	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
Invitae	RCV000586690	SCV000544683	pathogenic	Familial hypercholesterolemia	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 416 of the LDLR protein (p.Arg416Trp). This variant is present in population databases (rs570942190, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9104431, 9259195, 11196104, 11668640, 14974088, 17539906, 18700895, 20538126, 20663204, 21310417, 21376320, 23375686, 25378237, 25921077, 25962062, 26892515). This variant is also known as p.Arg395Trp. ClinVar contains an entry for this variant (Variation ID: 183110). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 25378237, 25647241). This variant disrupts the p.Arg416 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 20045108, 20538126), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211633	SCV000583812	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000211633	SCV000588568	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000211633	SCV000607579	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586690	SCV000697192	pathogenic	Familial hypercholesterolemia	2016-11-21	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.1246C>T (p.Arg416Trp) variant (alternatively also known as R395W) is located in the six-bladed beta-propeller, TolB-like domain of the protein (InterPro). 4/4 in silico tools predict a damaging outcome for this variant. Functional analyses conclude that this variant results in defective LDLR recycling (Etxebarria_2015). The variant is widely reported as a pathogenic variant in literature found across many countries (Schmidt_2000, Real_2003, Leren_2004, Charng_2006, Humphries_2006, Tichy_2012). Other missense changes at this codon, namely p.Arg416Leu, p.Arg416Pro and p.Arg416Gln have been associated with FH, supporting that the codon is likely to be a mutational hot-spot. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. This variant was found in 3/120616 control chromosomes at a frequency of 0.0000249, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0010005). The heterozygotes in ExAC are likely to represent as subclinical cases or reduced penetrance as it is recurrently found mutation in FH patients. Taken together, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825619	SCV000966971	pathogenic	Homozygous familial hypercholesterolemia	2019-03-03	criteria provided, single submitter	clinical testing	The p.Arg416Trp variant in LDLR has been reported in >30 individuals with familial hypercholesterolemia (FH) and segregated with disease in 1 affected relative (Day 1997, Dušková 2011, Tichý 2012, Bertolini 2013, Do 2015, Etxebarria 2015, Han 2015, Sánchez-Hernández 2016, Sharifi 2016, Durst 2017). It has also been reported by other clinical laboratories in ClinVar (Variation ID: 183110) and been identified in 3/30782 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs570942190). This frequency is low enough to be consistent with the frequency of FH in the general population. Amino acid position 416 is a known mutation hotspot, with many other variants (p.Arg416Pro, p.Arg416Leu and p.Arg416Gln) reported in individuals with FH (Liguori 2001, Bertolini 2013, Chiou 2010, Thiart 1998, Huijgen 2012). Functional studies provide some evidence that the p.Arg416Trp variant may impact protein function (Etxebarria 2015). In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon presence in multiple affected individuals, low frequency in the general population, functional and computational evidence and its presence in a known mutational hotspot. The ACMG/AMP criteria applied: PS4, PM1, PM2, PS3_Moderate, PP3 (Richards 2015).
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000211633	SCV001432555	pathogenic	Hypercholesterolemia, familial, 1	2019-03-13	criteria provided, single submitter	research
Mayo Clinic Laboratories, Mayo Clinic	RCV000161982	SCV001715245	pathogenic	not provided	2020-12-15	criteria provided, single submitter	clinical testing	PS4, PM1, PM2, PS3_Moderate, PP3
Color Diagnostics, LLC DBA Color Health	RCV000586690	SCV001733657	pathogenic	Familial hypercholesterolemia	2023-07-27	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Arg395Trp in the mature protein) replaces arginine with tryptophan at codon 416 in the LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant decreases LDLR cell surface expression and LDL uptake, and causes defective LDLR recycling due to protein degradation in lysosomes (PMID 25378237). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 9104431, 9259195, 11196104, 11668640, 14974088, 17539906, 18700895, 20538126, 20663204, 21310417, 21376320, 23375686, 25378237, 25921077, 25962062, 26892515, 27784735, 28104544, 32423031, 33740630, 33955087, 33994402, 34037665, 34407635, 34834584, 36499307). It has been shown that this variant segregates with hypercholesterolemia in multiple Norwegian families (PMID: 9104431). This variant has been identified in 6/251158 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg416Gln, is considered to be disease-causing (ClinVar variation ID: 251752), suggesting that arginine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic.
Ambry Genetics	RCV002390392	SCV002668658	pathogenic	Cardiovascular phenotype	2022-07-21	criteria provided, single submitter	clinical testing	The p.R416W pathogenic mutation (also known as c.1246C>T), located in coding exon 9 of the LDLR gene, results from a C to T substitution at nucleotide position 1246. The arginine at codon 416 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration, also known as R395W, has been described in a number of hypercholesterolemic individuals worldwide, and has been reported to segregate with the disease in several families (Day IN et al. Hum. Mutat., 1997;10:116-27; Leren TP et al. J. Intern. Med., 1997 Mar;241:185-94; Schmidt H et al. Atherosclerosis, 2000 Feb;148:431-2; Weiss N et al. J. Inherit. Metab. Dis., 2000 Dec;23:778-90; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; García-García AB et al. Hum. Mutat., 2001 Nov;18:458-9; Wang J et al. Hum. Mutat., 2001 Oct;18:359; Dedoussis GV et al. Hum. Mutat., 2004 Mar;23:285-6; Chiou KR et al. Am. J. Cardiol., 2010 Jun;105:1752-8; Goldmann R et al. BMC Med. Genet., 2010 Jul;11:115; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Shin DG et al. Atherosclerosis, 2015 Nov;243:53-8; Han Y et al. Int. J. Pediatr. Otorhinolaryngol., 2015 Jul;79:1148-51; Sharifi M et al. Metab. Clin. Exp., 2016 Mar;65:48-53). In addition, functional studies have indicated this alteration would affect protein recycling, causing reduced LDLR membrane expression and thus reduced ligand uptake (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.
Revvity Omics, Revvity	RCV000211633	SCV003827839	pathogenic	Hypercholesterolemia, familial, 1	2022-11-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000161982	SCV003840656	pathogenic	not provided	2022-09-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest defective receptor recycling, membrane localization, binding activity, and LDL particle uptake (Etxebarria et al., 2015; Thormaehlen et al., 2015; Galicia-Garcia et al., 2020; Duskova et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as R395W; This variant is associated with the following publications: (PMID: 9259195, 17539906, 18700895, 25921077, 26892515, 34407635, 32423031, 35339733, 33391333, 33133164, 23375686, 25487149, 25647241, 9104431, 11196104, 11668640, 14974088, 20045108, 20663204, 21310417, 28104544, 28965616, 30592178, 29531935, 31447099, 20538126, 32015373, 32629184, 32695144, 32041611, 33303402, 32331935, 33740630, 33418990, 34037665, 34456049, 35913489, 33955087, 33994402, 25378237)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000161982	SCV004219941	pathogenic	not provided	2023-04-21	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000098 (3/30616 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with familial or isolated hypercholesterolemia (PMIDs: 36901902 (2023), 34456049 (2022), 35913489 (2022), 35339733 (2022), 33955087 (2021), 34407635 (2021), 33303402 (2021), 33994402 (2021) 33418990 (2021), 34037665 (2021), 33740630 (2021), 32423031 (2020), 31447099 (2019), 30592178 (2019), 31345425 (2019), 29531935 (2018), 28104544 (2017)). Functional studies show the variant impacts LDLR expression and binding (PMIDs: 25378237 (2015)). 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, this variant is classified as pathogenic.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161982	SCV000189557	not provided	not provided		no assertion provided	in vitro
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211633	SCV000268608	pathogenic	Hypercholesterolemia, familial, 1	2012-05-22	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211633	SCV000606372	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research