ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1246C>T (p.Arg416Trp) (rs570942190)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211633 SCV000268608 pathogenic Familial hypercholesterolemia 2012-05-22 no assertion criteria provided 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 Familial hypercholesterolemia 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
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161982 SCV000189557 not provided not provided no assertion provided in vitro
Fundacion Hipercolesterolemia Familiar RCV000211633 SCV000607579 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000211633 SCV000410532 pathogenic Familial hypercholesterolemia 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.
Integrated Genetics/Laboratory Corporation of America RCV000586690 SCV000697192 pathogenic Familial hypercholesterolemias 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.
Invitae RCV000586690 SCV000544683 pathogenic Familial hypercholesterolemias 2018-08-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 416 of the LDLR protein (p.Arg416Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs570942190, ExAC 0.009%). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 20663204, 23375686, 21376320, 9104431, 25378237, 25921077, 11196104, 14974088, 21310417, 18700895, 17539906, 26892515, 25962062, 11668640, 20538126, 9259195). This variant is also known as p.Arg395Trp in the literature. ClinVar contains an entry for this variant (Variation ID: 183110). Experimental studies have shown that this missense change causes low LDLR expression at the membrane surface and reduced efficiency of LDL uptake both in transfected cells and in an individual with this variant.  In transfected cells, this variant caused LDLR to be degraded rather than be recycled (PMID: 25378237). However, another study shows that there is little effect on LDL uptake (PMID: 25647241). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Other missense substitutions at this codon (p.Arg416Pro and p.Arg416Leu) have been reported in individuals affected with familial hypercholesterolemia (PMID: 20045108, 20538126). For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000211633 SCV000295325 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211633 SCV000606372 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000825619 SCV000966971 pathogenic Familial hypercholesterolemia - homozygous 2018-01-19 criteria provided, single submitter clinical testing The p.Arg416Trp variant in LDLR has been reported in >30 individuals with famili al hypercholesterolemia (FH) and segregated with disease in 1 affected relative (Day 1997, Duskova 2011, Tichy 2012, Bertolini 2013, Do 2015, Etxebarria 2015, H an 2015, Sanchez-Hernandez 2016, Sharifi 2016, Durst 2017). It has also been rep orted 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 populatio n. 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 (Lig uori 2001, Bertolini 2013, Chiou 2010, Thiart 1998, Huijgen 2012). Functional st udies provide some evidence that the p.Arg416Trp variant may impact protein func tion (Etxebarria 2015). In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon presence in mul tiple affected individuals, low frequency in the general population, functional and computational evidence and its presence in a known mutational hotspot. ACMG/ AMP criteria applied: PS4, PM1, PM2, PS3_Moderate, PP3 (Richards 2015).
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000211633 SCV000588568 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000211633 SCV000540805 likely pathogenic Familial hypercholesterolemia 2016-11-05 criteria provided, single submitter clinical testing
Robarts Research Institute,Western University RCV000211633 SCV000484694 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211633 SCV000583812 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

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