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

Total submissions: 15

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
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, http://gnomad.broadinstitute.org; 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).