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

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211633	SCV000295325	likely pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Illumina Clinical Services Laboratory,Illumina	RCV000211633	SCV000410532	pathogenic	Familial hypercholesterolemia 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	Familial hypercholesterolemia 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	Familial hypercholesterolemia 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	Familial hypercholesterolemia 1	2016-11-05	criteria provided, single submitter	clinical testing
Invitae	RCV000586690	SCV000544683	pathogenic	Familial hypercholesterolemia	2019-12-31	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.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211633	SCV000583812	pathogenic	Familial hypercholesterolemia 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000211633	SCV000588568	likely pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000211633	SCV000607579	likely pathogenic	Familial hypercholesterolemia 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, Partners HealthCare 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	Familial hypercholesterolemia 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 Health, Inc	RCV000586690	SCV001733657	pathogenic	Familial hypercholesterolemia	2020-11-17	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 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 20 individuals affected with familial hypercholesterolemia (PMID: 9104431, 9104431, 9259195, 11196104, 11668640, 14974088, 17539906, 18700895, 20538126, 20663204, 21310417, 21376320, 23375686, 25378237, 25921077, 25962062, 26892515, 27784735, 28104544, 32423031). 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). Based on the available evidence, 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	Familial hypercholesterolemia 1	2012-05-22	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000211633	SCV000606372	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research