ClinVar Miner

Submissions for variant NM_000527.5(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
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 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 RCV000237883 SCV000503344 likely benign Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / Software predictions: Conflicting
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000237883 SCV000540817 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844749 SCV000731720 likely pathogenic Homozygous familial hypercholesterolemia 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000161988 SCV000888161 likely pathogenic not provided 2018-05-04 criteria provided, single submitter clinical testing
Color RCV000775068 SCV000909169 likely pathogenic Familial hypercholesterolemia 2020-03-11 criteria provided, single submitter clinical testing
Invitae RCV000775068 SCV001227232 uncertain significance Familial hypercholesterolemia 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 472 of the LDLR protein (p.Asp472Tyr). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs730882102, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed to segregate with hypercholesterolemia in families (PMID: 17196209, 27542166). This variant is also known as p.D451Y and p.D304Y in the literature. ClinVar contains an entry for this variant (Variation ID: 183116). This variant has been reported to affect LDLR protein function (PMID: 25647241). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161988 SCV000189563 not provided not provided no assertion provided in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237883 SCV000606418 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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