ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser) (rs730882106)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238217 SCV000295505 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 RCV000238217 SCV000503367 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 4 , family members = 3 / FH-Cincinnati-3, 5% to 15% LDLR Activity / Software predictions: Damaging
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000455448 SCV000539511 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 3 papers, 1 describing in vitro study suggesting functional impact, 1 report in a control. Reported in ExAC: 2/66098 European chromosomes
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000238217 SCV000583850 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Invitae RCV000775072 SCV000627019 pathogenic Familial hypercholesterolemia 2020-08-14 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 526 of the LDLR protein (p.Pro526Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs730882106, ExAC 0.003%). This variant has been reported in several unrelated individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 11462246, 27497240, Invitae). This variant is also known as p.Pro505Ser in the literature. ClinVar contains an entry for this variant (Variation ID: 183120). Experimental studies have shown that this missense change has a deleterious effect on LDLR expression and leads to significantly impaired activity (PMID: 1301956, 25647241). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000775072 SCV000909174 likely pathogenic Familial hypercholesterolemia 2019-04-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000161994 SCV001134254 likely pathogenic not provided 2019-06-25 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Found in at least one symptomatic patient. At least one other pathogenic or likely pathogenic variant affects the same amino acid. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000238217 SCV001432657 likely pathogenic Familial hypercholesterolemia 1 2019-03-03 criteria provided, single submitter research
GeneDx RCV000161994 SCV001792713 likely pathogenic not provided 2019-06-10 criteria provided, single submitter clinical testing Reported in several individuals with FH, some of which harbored an additional FH-related variant; of note, this variant is also described as P505S and FH-Cincinnati-3 due to alternate nomenclature (Hobbs et al., 1992; Day et al., 1997; Nauck et al., 2001; Thormaehlen et al., 2015; Maurer et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar (ClinVar Variant ID# 183120; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate this variant impairs LDLR expression and results in significantly diminished LDLR activity (Hobbs et al., 1992; Thormaehlen et al., 2015); This variant is associated with the following publications: (PMID: 31447099, 30586733, 11462246, 9259195, 25647241, 1301956, 25487149, 27497240)
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161994 SCV000189569 not provided not provided no assertion provided in vitro
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals RCV000238217 SCV000680104 likely pathogenic Familial hypercholesterolemia 1 2017-05-29 no assertion criteria provided clinical testing

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