ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.757C>T (p.Arg253Trp)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute for Integrative and Experimental Genomics,University of Luebeck RCV000172958 SCV000212133 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter research
Cardiovascular Biomarker Research Laboratory,Mayo Clinic RCV000172958 SCV000266312 uncertain significance Familial hypercholesterolemia 1 2016-08-31 criteria provided, single submitter research MAF =<0.3%, likely pathogenic based on the integrative in-silico score. "Little/No effect" on the LDL receptor activity based on experimental validation.
LDLR-LOVD, British Heart Foundation RCV000172958 SCV000294952 uncertain significance Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000172958 SCV000583735 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000172958 SCV000588516 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV001085872 SCV001001882 likely benign Familial hypercholesterolemia 2019-12-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000162019 SCV001151652 likely benign not provided 2017-04-01 criteria provided, single submitter clinical testing
Color RCV001085872 SCV001344871 uncertain significance Familial hypercholesterolemia 2019-08-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001201284 SCV001372403 likely benign not specified 2020-06-30 criteria provided, single submitter clinical testing Variant summary: LDLR c.757C>T (p.Arg253Trp) results in a non-conservative amino acid change located in a class A repeat (IPR002172) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 251484 control chromosomes, predominantly at a frequency of 0.0012 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is higher (~1.2 fold) than the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Early Onset Coronary Artery Disease phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Though the variant, c.757C>T, has been reported in the literature in individuals affected with Hypercholesterolemia and/or Early Onset Coronary Artery Disease, later studies revealed that the variant didn't meet any of the three proposed criteria for association with Familial Hypercholesterolemia (see Huijgen_2010, Huijgen_2012 and the Jojo Genetics database). At least one publication reports experimental evidence evaluating an impact on protein function, and these results showed no damaging effect of this variant (Thormaehlen_2015). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000162019 SCV000189622 not provided not provided no assertion provided in vitro
CSER _CC_NCGL, University of Washington RCV000148562 SCV000190275 likely benign Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000172958 SCV000606216 benign Familial hypercholesterolemia 1 no assertion criteria provided research

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