ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1745T>C (p.Leu582Pro) (rs875989930)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211698 SCV000295631 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000211698 SCV000484721 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000211698 SCV000503406 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1/software prediction damaging
Color RCV000775075 SCV000909177 likely pathogenic Familial hypercholesterolemia 2019-03-22 criteria provided, single submitter clinical testing
Invitae RCV000775075 SCV000957611 likely pathogenic Familial hypercholesterolemia 2019-09-13 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 582 of the LDLR protein (p.Leu582Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 11668627, 15199436, 27765764). This variant is also known as L561P in the literature. ClinVar contains an entry for this variant (Variation ID: 226372). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211698 SCV000268635 pathogenic Familial hypercholesterolemia 1 2012-08-07 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000775075 SCV001422865 uncertain significance Familial hypercholesterolemia 2020-01-22 no assertion criteria provided curation The p.Leu582Pro variant in LDLR has been reported in 4 European individuals with familial hypercholesterolemia (PMID: 28161202, 15199436, 11668627), and was absent from large population studies. This variant has also been reported in ClinVar as likely pathogenic (Variation ID: 226372). 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, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS4_supporting (Richards 2015).

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