ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1414G>T (p.Asp472Tyr) (rs730882102)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237883 SCV000503344 likely benign Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / Software predictions: Conflicting
Color RCV000237883 SCV000689762 likely pathogenic Familial hypercholesterolemia 2017-08-29 criteria provided, single submitter clinical testing Likely Pathogenic variant based on current evidence: This variant (also known as p.Asp451Tyr in the mature protein) is a missense variant located in LDLR-B (YWTD) repeat 2 of EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Functional assays have demonstrated that the variant protein is partially defective in LDLR activity assay due to impaired expression or turnover (PMID 25647241). This variant has been reported in the literature in multiple unrelated American, Italian and Czech individuals diagnosed with FH (PMID 17196209, 21310417, 22698793, 23375686, 27542166, 28008010) and segregated in 5 affected relatives in two families. This variant has also been identified in 10/121250 chromosomes by the Exome Aggregation Consortium (ExAC) general population database.
Color RCV000775068 SCV000909169 likely pathogenic Familial hypercholesterolemias 2018-05-15 criteria provided, single submitter clinical testing Likely Pathogenic variant based on current evidence: This missense variant (also known as p.Asp451Tyr in the mature protein) is located in the LDLR-B repeat 2 in the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. An experimental study has demonstrated that the variant protein is partially defective in LDLR activity due to impaired expression or turnover (PMID: 25647241). This variant has been reported in multiple unrelated individuals diagnosed with familial hypercholesterolemia (PMID: 17196209, 21310417, 22698793, 23375686, 27542166, 28008010) and segregated in 5 affected relatives in two families (PMID: 17196209, 27542166). This variant has been identified in 14/276984 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161988 SCV000189563 not provided not provided no assertion provided in vitro
GeneDx RCV000161988 SCV000234649 pathogenic not provided 2016-06-22 criteria provided, single submitter clinical testing The D472Y c.1414 GAC>TAC variant in the LDLR gene has been published previously as a disease-causing variant in association with hypercholesterolemia (Campagna et al., 2008; Bertolini et al., 2013). Based on the ACMG recommendations, D472Y is interpreted as a known pathogenic sequence change.
LDLR-LOVD, British Heart Foundation RCV000237883 SCV000295416 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237883 SCV000606418 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844749 SCV000731720 likely pathogenic Familial hypercholesterolemia - homozygous 2017-08-03 criteria provided, single submitter clinical testing The p.Asp472Tyr variant in LDLR (also described as p.Asp451Tyr in the literature ) has been reported in 10 individuals with familial hypercholesterolemia (FH) an d 12 individuals who had a myocardial infarction, and segregated with disease in 3 affected relatives from 2 families (Abul-Husn 2016, Vohnout 2016, Thormaehlen 2015, Tichy 2012, Bertolini 2013, Do 2015, Campagna 2008). This variant has als o been reported by other clinical laboratories in ClinVar (Variation ID 183116) and has been identified in 5/30778 of South Asian chromosomes and 8/126504 Europ ean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadi nstitute.org/; dbSNP 730882102). This frequency is low enough to be consistent w ith the frequency of FH in the general population. Computational prediction tool s and conservation analysis do not provide strong support for or against an impa ct to the protein and in vitro functional assays were unclear in their overall i mpact (Thormaehlen 2015). In summary, although additional studies are required t o fully establish its clinical significance, the p.Asp472Tyr variant is likely p athogenic. ACMG/AMP Criteria applied (Richards 2015): PS4, PM2, PP1.
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000237883 SCV000540817 likely pathogenic Familial hypercholesterolemia 2016-11-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000161988 SCV000888161 likely pathogenic not provided 2018-05-04 criteria provided, single submitter clinical testing

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