ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1444G>A (p.Asp482Asn) (rs139624145)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute for Integrative and Experimental Genomics,University of Luebeck RCV000172963 SCV000212139 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter research
LDLR-LOVD, British Heart Foundation RCV000172963 SCV000295433 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000172963 SCV000484754 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
GeneDx RCV000414235 SCV000491201 pathogenic not provided 2018-08-24 criteria provided, single submitter clinical testing The D482N variant in the LDLR gene, also reported as D461N due to alternate nomenclature, has been previously reported in both the heterozygous and compound heterozygous state in multiple individuals with FH (Ward et al., 1995; Webb et al., 1996; Bochmann et al., 2001; Fouchier et al., 2001; Laurie et al., 2004; Graham et al., 2005; Taylor et al., 2010; Hooper et al., 2012; Tichy et al., 2012; Bertolini et al., 2013; Braene et al., 2016; Wang et al., 2016; Thedrez et al., 2018). It has also been shown to segregate with FH in multiple affected heterozygous relatives from multiple families (Ward et al., 1995; Webb et al., 1996; Braene et al., 2016). The D482N variant has been observed in 11/126,622 alleles (0.01%) from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016). Located in the LDL-receptor class B repeat 2 region of the LDLR gene, the D482N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function and functional studies showed that D482N, when seen in the homozygous or compound heterozygous states, results in decreased LDL receptor activity (Webb et al., 1996). Moreover, likely pathogenic missense variants at the same residue (D482H, D482Y) have also been reported in association with FH (Day et al., 1997; Meshov et al., 2004), supporting the functional importance of this residue.
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000172963 SCV000540819 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
Invitae RCV000775070 SCV000544697 pathogenic Familial hypercholesterolemia 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 482 of the LDLR protein (p.Asp482Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs139624145, ExAC <0.01%). This variant has been reported in the literature in several unrelated individuals affected with hypercholesterolemia (PMID: 8535447, 23375686, 21310417, 20236128, 16389549). This variant is also known as p.Asp461Asn in the literature. ClinVar contains an entry for this variant (Variation ID: 161284). A different missense substitution at this codon (p.Asp482His) has been determined to be pathogenic (PMID: 21310417, 20236128, 16389549). This suggests that the aspartic acid residue is critical for LDLR protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000172963 SCV000583832 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Fundacion Hipercolesterolemia Familiar RCV000172963 SCV000607600 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Iberoamerican FH Network RCV000172963 SCV000748149 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000172963 SCV000839981 likely pathogenic Familial hypercholesterolemia 1 2017-05-11 criteria provided, single submitter clinical testing The c.1444G>A (p.Asp482Asn) variant in the LDLR gene has been reported in patients with hypercholesterolemia [PMID 8535447, 23375686, 20236128, 16159606, 21326404; legacy name 461]. This variant was observed in five heterozygous individuals in the ExAC population database (http://exac.broadinstitute.org/variant/19-11224296-G-A). Aspartate at position 482 of the LDLR protein is conserved in mammals and while not clinically validated, computer-based algorithms (SIFT and Polyphen-2) predict this p.Asp482Asn change to be deleterious. This c.1444G>A (p.Asp482Asn) variant is thus classified as likely pathogenic.
Color RCV000775070 SCV000909171 likely pathogenic Familial hypercholesterolemia 2020-04-27 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000172963 SCV000914825 pathogenic Familial hypercholesterolemia 1 2017-09-11 criteria provided, single submitter clinical testing Across a selection of the available literature, the LDLR c.1444G>A (p.Asp482Asn) variant has been identified in a heterozygous state in 36 cases with familial hypercholesterolemia (Taylor et al. 2010; Martin et al. 2016; Braenne et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000087 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Asp482Asn 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 RCV000775070 SCV000917587 pathogenic Familial hypercholesterolemia 2018-09-05 criteria provided, single submitter clinical testing Variant summary: LDLR c.1444G>A (p.Asp482Asn) results in a conservative amino acid change located in the LDLR class B repeat of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 277372 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (4e-05 vs 0.0013), allowing no conclusion about variant significance. c.1444G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Bochmann_2001, Bunn_2002, Fouchier_2001, Graham_1999, Graham_2005, Martin_2016, Ward_1995). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV000172963 SCV001251401 likely pathogenic Familial hypercholesterolemia 1 2019-10-16 criteria provided, single submitter clinical testing
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000172963 SCV001432632 likely pathogenic Familial hypercholesterolemia 1 2019-05-11 criteria provided, single submitter research
CSER _CC_NCGL, University of Washington RCV000148591 SCV000190305 uncertain significance Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000172963 SCV000268616 pathogenic Familial hypercholesterolemia 1 2008-07-22 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000172963 SCV000606428 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Broad Institute Rare Disease Group,Broad Institute RCV000172963 SCV001423103 likely pathogenic Familial hypercholesterolemia 1 2020-01-22 no assertion criteria provided curation The p.Asp482Asn (sometimes called p.Asp461Asn) variant in LDLR has been reported in at least 24 individuals (including 4 Czech, 3 German, 1 Norwegian, 1 Italian, and 1 Dutch individuals) with Familial Hypercholesterolemia, segregated with disease in 5 affected relatives from 2 families (PMID: 26036859, 22698793, 9026534, 15199436, 11857755, 16159606, 21310417, 11139254, 11810272), and has been identified in 0.008526% (11/129018) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs139624145). 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 as a VUS, a likely pathogenic variant, and a pathogenic variant in ClinVar (Variation ID: 161284). 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, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PP1_Moderate, PP3 (Richards 2015).

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