ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1216C>T (p.Arg406Trp)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211575 SCV000295306 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211575 SCV000322937 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/208 non-FH alleles; 0/100 healthy control individuals
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000211575 SCV000503317 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 11 , family members = 7 with co-segregation / previously described in association with FH/Software predictions: Benign
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211575 SCV000583806 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000211575 SCV000588566 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000211575 SCV000607575 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Iberoamerican FH Network RCV000211575 SCV000748143 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000211575 SCV000987565 pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Invitae RCV001045722 SCV001209593 pathogenic Familial hypercholesterolemia 2019-09-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 406 of the LDLR protein (p.Arg406Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs121908043, ExAC 0.01%). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 8882879, 25461735, 26343872, 25741862, 20538126, Invitae). This variant is also known as R385W in the literature. ClinVar contains an entry for this variant (Variation ID: 226351). This variant has been reported to affect LDLR protein function (PMID: 25741862). This variant disrupts the p.Arg406 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 16250003), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000211575 SCV001432550 pathogenic Familial hypercholesterolemia 1 2018-12-07 criteria provided, single submitter research
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211575 SCV000268604 pathogenic Familial hypercholesterolemia 1 2012-07-04 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211575 SCV000606362 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Broad Institute Rare Disease Group,Broad Institute RCV000211575 SCV001422933 pathogenic Familial hypercholesterolemia 1 2020-01-22 no assertion criteria provided curation The p.Arg406Trp variant in LDLR has been reported in at least 51 individuals (including 48 Portuguese, 1 Taiwanese, 1 Korean, and 1 Ashkenazi Jewish individuals) with Familial Hypercholesterolemia, segregated with disease in 48 affected relatives from 18 families (PMID: 17765246, 20538126, 26343872, 8882879, 25741862), and has been identified in 0.009658% (1/10354) of Ashkenazi Jewish chromosomes and 0.008021% (2/24936) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908043). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic and pathogenic in ClinVar (Variation ID: 226351). In vitro functional studies provide some evidence that the p.Arg406Trp variant may impact cell surface expression and receptor activity (PMID: 25741862). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on cosegregation with disease and multiple reports in individuals with Familial Hypercholesterolemia. ACMG/AMP Criteria applied: PP1_Strong, PS4, PS3_supporting, PP3 (Richards 2015).

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