ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.858C>A (p.Ser286Arg) (rs140241383)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237148 SCV000295013 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000237148 SCV000484736 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 RCV000237148 SCV000503244 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 6 / FH-Greece-2, 5 to 15% LDLR Activity / Software predictions: Conflicting
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000237148 SCV000540765 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237148 SCV000583749 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590088 SCV000697254 pathogenic Familial hypercholesterolemia 2017-04-06 criteria provided, single submitter clinical testing Variant summary: The LDLR c.858C>A (p.Ser286Arg) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index), which was confirmed by low LDLR activity in patient carrying this variant (Hobbs_1992). This variant was found in 3/121368 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been reported in a large number of FH patients with milder phenotype. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000590088 SCV000752422 likely pathogenic Familial hypercholesterolemia 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 286 of the LDLR protein (p.Ser286Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is present in population databases (rs140241383, ExAC 0.004%). This variant has been reported in several individuals affected with familial hypercholesterolemia (FH) (PMID: 1301956, 11317361, 11462246, 15015036, 23130880, 27765764). This variant is also known as p.Ser265Arg in the literature. ClinVar contains an entry for this variant (Variation ID: 251488). 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000237148 SCV000987682 pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985771 SCV001134271 pathogenic not provided 2019-05-24 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Color Health, Inc RCV000590088 SCV001358587 pathogenic Familial hypercholesterolemia 2019-03-15 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000237148 SCV001429319 uncertain significance Familial hypercholesterolemia 1 2019-02-14 criteria provided, single submitter clinical testing
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000237148 SCV001432669 pathogenic Familial hypercholesterolemia 1 2019-05-23 criteria provided, single submitter research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237148 SCV000606249 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Clinical Genetics,Academic Medical Center RCV000985771 SCV001918117 pathogenic not provided no assertion criteria provided clinical testing

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