ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1576C>T (p.Pro526Ser) (rs730882106)

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Total submissions: 8
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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 RCV000238217 SCV000503367 likely pathogenic Familial hypercholesterolemia 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
Color RCV000775072 SCV000909174 likely pathogenic Familial hypercholesterolemias 2018-09-24 criteria provided, single submitter clinical testing Likely Pathogenic variant based on current evidence: This missense variant (also known as p.Pro505Ser in the mature protein; FH Cincinnati-3) is located in the third 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. An experimental functional study has shown a significantly reduced LDLR activity (5-15% of the wild type) in cells from a heterozygous hypercholesterolemic subject (PMID: 1301956). This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 11462246, 27497240). This variant is rare in the general population and has been identified in 3/277044 chromosomes 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 RCV000161994 SCV000189569 not provided not provided no assertion provided in vitro
Invitae RCV000238217 SCV000627019 pathogenic Familial hypercholesterolemia 2017-03-07 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.
LDLR-LOVD, British Heart Foundation RCV000238217 SCV000295505 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
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
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals RCV000238217 SCV000680104 likely pathogenic Familial hypercholesterolemia 2017-05-29 no assertion criteria provided clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000238217 SCV000583850 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

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