ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.81C>G (p.Cys27Trp) (rs2228671)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211569 SCV000294455 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000211569 SCV000484735 likely pathogenic Familial hypercholesterolemia 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 RCV000211569 SCV000503098 likely benign Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000211569 SCV000540716 likely pathogenic Familial hypercholesterolemia 2016-11-05 criteria provided, single submitter clinical testing Disrupt disulfide bridge between Cys27 and Cys39.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211569 SCV000583627 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing ACMG Guidelines: Pathogenic (ii)
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000211569 SCV000588483 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000211569 SCV000607412 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000588365 SCV000697253 pathogenic Familial hypercholesterolemias 2017-01-12 criteria provided, single submitter clinical testing Variant summary: The LDLR c.81C>G (p.Cys27Trp) variant (alternatively also known as C6W and FH San Francisco) substitutes a Cys residue located in LDL receptor class A repeat which forms ligand binding domain (InterPro, Klancar_2015, Bertolini_2013, Hobbs_1992). The ligand-binding domain contains seven or eight 40-amino acid LDLR class A (cysteine-rich) repeats, each of which contains a coordinated calcium ion and six cysteine residues involved in disulphide bond formation (InterPro, PMID: 6091915). Therefore, this variant is predicted to be deleterious for protein function as it breaks down one of the disulphide bonds. 5/5 in silico tools also predict damaging outcome for this variant. This variant was found in 2/121358 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). In literature, this variant is widely reported as a pathogenic variant found mainly in FH patients of European origin (Klancar_2015, Mollaki_2014,Kolansky_2008, Bertolini_2013, Day_1997, Hobbs_1992). Genotype-phenotype correlation study showed that this variant causes a milder disease (Mollaki_2014). A functional study showed that this variant leads to impaired LDL receptor activity (Hobbs_1992). Multiple reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as Pathogenic.
Department of Human Genetics,Laborarztpraxis Dres. Walther, Weindel und Kollegen RCV000211569 SCV000987032 likely pathogenic Familial hypercholesterolemia 2018-08-06 criteria provided, single submitter clinical testing The mutation at the protein level at position 27 (position 6 of the mature protein) leads to the amino acid change of cysteine to tryptophan (p.Cys27Trp, old nomenclature: p.Cys6Trp). This change has already been described in the literature as a San Francisco allele and is associated with elevated cholesterol and LDL-C levels. Impairment of LDL receptor activity has been demonstrated. We observed a patient with that kind of mutation with average values of TC = 330 and LDL-C of 280 mg/dl. PMID: 1301956, 23375686, 27497240
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000211569 SCV000987521 pathogenic Familial hypercholesterolemia criteria provided, single submitter clinical testing
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211569 SCV000268538 pathogenic Familial hypercholesterolemia 2012-04-16 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211569 SCV000606006 pathogenic Familial hypercholesterolemia no assertion criteria provided research

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