ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1745T>C (p.Leu582Pro) (rs875989930)

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Total submissions: 6
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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 2018-08-28 criteria provided, single submitter clinical testing Likely Pathogenic variant based on current evidence: This missense variant (also known as p.Leu561Pro in the mature protein) is located in the fifth LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 11668627, 15199436, 15576851, 17353666, 28161202, 27765764). This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.
Invitae RCV000775075 SCV000957611 likely pathogenic Familial hypercholesterolemia 2018-07-16 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

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