ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.81C>G (p.Cys27Trp)

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Total submissions: 17
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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 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000211569 SCV000484735 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 RCV000211569 SCV000503098 likely benign Familial hypercholesterolemia 1 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 1 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 1 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 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000211569 SCV000607412 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000588365 SCV000697253 pathogenic Familial hypercholesterolemia 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 1 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 1 criteria provided, single submitter clinical testing
Invitae RCV000588365 SCV001225810 pathogenic Familial hypercholesterolemia 2019-12-04 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tryptophan at codon 27 of the LDLR protein (p.Cys27Trp). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and tryptophan. This variant is present in population databases (rs2228671, ExAC 0.003%). This variant has been observed in several individuals affected with hypercholesterolemia (PMID: 27497240, 14974088, 27824480, 25463123, 11668627, 19026292). This variant is also known as C6W in the literature. ClinVar contains an entry for this variant (Variation ID: 226304). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domain of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). For these reasons, this variant has been classified as Pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000211569 SCV001432579 likely pathogenic Familial hypercholesterolemia 1 2019-01-21 criteria provided, single submitter research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000588365 SCV001434982 likely pathogenic Familial hypercholesterolemia 2018-10-02 criteria provided, single submitter clinical testing This c.81C>G (p.Cys27Trp) variant in the LDLR gene has been reported in multiple unrelated individuals with familial hypercholesterolemia (PMID: 1301956, 9259195, 11317361, 11668627, 16250003, 23375686) and is extremely rare in the general population. Functional studies have reported that the mutant LDLR protein retains 15-30% of receptor activity compared with wildtype LDLR protein (PMID: 1301956). Therefore, this c.81C>G (p.Cys27Trp) variant in the LDLR gene is classified as likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001283999 SCV001469538 pathogenic not provided 2020-06-30 criteria provided, single submitter clinical testing Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211569 SCV000268538 pathogenic Familial hypercholesterolemia 1 2012-04-16 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211569 SCV000606006 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Broad Institute Rare Disease Group,Broad Institute RCV000211569 SCV001422932 pathogenic Familial hypercholesterolemia 1 2020-01-22 no assertion criteria provided curation The p.Cys27Trp variant in LDLR has been reported in 54 individuals (including 47 Greek individuals) with Familial Hypercholesterolemia (PMID: 11317361, 11668627, 9259195, 1301956, 25463123, 19026292), segregated with disease in 37 affected relatives from 18 families, and has been identified in 0.003518% (4/113686) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs2228671). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic, likely pathogenic, and likely benign in ClinVar (Variation ID: 226304). In vitro functional studies provide some evidence that the p.Cys27Trp variant may slightly impact protein function (PMID: 1301956). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on cosegregation with Familial Hypercholesterolemia and greater prevalence in individuals with Familial Hypercholesterolemia than in control cohorts. ACMG/AMP Criteria applied: PS4, PP1_Strong, PP3, PS3_supporting (Richards 2015).

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