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

Total submissions: 14

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	2020-06-15	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
GeneDx	RCV001560136	SCV001782484	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that R406W results in decreased LDLR expression and well as reduced LDL binding and uptake, and is describe as a mild pathogenic variant (Benito-Vicente et al., 2015); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32331935, 32719484, 31589614, 31491741, 30876530, 30586733, 20538126, 26343872, 19318025, 17765246, 8882879, 25741862)
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).