ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1329G>C (p.Trp443Cys) (rs879254867)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 11
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237729 SCV000295371 likely pathogenic Familial hypercholesterolemia 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 RCV000237729 SCV000503334 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 10 , family members = 5 with co-segregation / previously described in association with FH / Software predictions: Damaging
Invitae RCV000791422 SCV000544664 pathogenic Familial hypercholesterolemia 2019-08-12 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 443 of the LDLR protein (p.Trp443Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in several individuals affected with hypercholesterolemia (PMID: 1301956, 11196104, 9664576, 9727746, 22390909). This variant is also known as p.Trp422Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 251792). 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. The observation of one or more missense substitutions at this codon (p.Trp443) in affected individuals suggests that this may be a clinically significant residue (PMID: 28458923). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000494596 SCV000583130 pathogenic not provided 2018-03-21 criteria provided, single submitter clinical testing The W443C pathogenic variant in the LDLR gene has been reported in multiple unrelated patients with FH (Hobbs et al., 1992; Callis et al., 1998; Nissen et al., 1998; Weiss et al., 2000; Vergotine et al., 2001; Amsellem et al., 2002; van der Graaf et al., 2011). Located within the LDL-receptor class B repeat 2 region of the protein, the W443C variant results in a non-conservative amino acid substitution at a position that is conserved across species. Additionally, a different nucleotide substitution (c.1329 G>T) that also results in the W443C missense substitution was previously identified in association with FH, supporting the functional importance of this position in the protein (Fouchier et al., 2001). Variants in the same residue (W443S, W443R) have been reported in HGMD in association with FH (Stenson et al., 2014), further supporting the functional importance of this residue of the protein. Furthermore, the W443C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237729 SCV000583822 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844741 SCV000731444 pathogenic Homozygous familial hypercholesterolemia 2017-01-31 criteria provided, single submitter clinical testing The p.Trp443Cys variant in LDLR has been reported in >90 individuals with famili al hypercholesterolemia (FH) and was absent from large population studies. In vi tro functional studies demonstrate that this variant results in reduced protein activity (Hobbs 1992). Computational prediction tools and conservation analysis suggest that the p.Trp443Cys variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dom inant manner based upon prevalence among probands, absence from controls, and fu nctional evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000494596 SCV001134249 pathogenic not provided 2019-06-05 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/282626 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Multiple pathogenic or likely pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000494596 SCV001246007 pathogenic not provided 2017-01-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000791422 SCV001346787 pathogenic Familial hypercholesterolemia 2019-10-24 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000237729 SCV001440625 pathogenic Familial hypercholesterolemia 1 2019-01-01 criteria provided, single submitter clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237729 SCV000606396 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.