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The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification

2022-02Journal article Restricted access
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dc.contributor.authorChora, Joana R.
dc.contributor.authorIacocca, Michael A.
dc.contributor.authorTichý, Lukáš
dc.contributor.authorWand, Hannah
dc.contributor.authorKurtz, C. Lisa
dc.contributor.authorZimmermann, Heather
dc.contributor.authorLeon, Annette
dc.contributor.authorWilliams, Maggie
dc.contributor.authorHumphries, Steve E.
dc.contributor.authorHooper, Amanda J.
dc.contributor.authorTrinder, Mark
dc.contributor.authorBrunham, Liam R.
dc.contributor.authorCosta Pereira, Alexandre
dc.contributor.authorJannes, Cinthia E.
dc.contributor.authorChen, Margaret
dc.contributor.authorChonis, Jessica
dc.contributor.authorWang, Jian
dc.contributor.authorKim, Serra
dc.contributor.authorJohnston, Tami
dc.contributor.authorSoucek, Premysl
dc.contributor.authorKramarek, Michal
dc.contributor.authorLeigh, Sarah E.
dc.contributor.authorCarrié, Alain
dc.contributor.authorSijbrands, Eric J.
dc.contributor.authorHegele, Robert A.
dc.contributor.authorFreiberger, Tomáš
dc.contributor.authorKnowles, Joshua W.
dc.contributor.authorBourbon, Mafalda
dc.contributor.authorClinGen Familial Hypercholesterolemia Expert Panel
dc.date.accessioned2022-10-31T14:54:56Z
dc.date.available2022-10-31T14:54:56Z
dc.date.issued2022-02
dc.descriptionThe online version of this article (https://doi.org/10.1016/j. gim.2021.09.012) contains supplementary material, which is available to authorized users.pt_PT
dc.description.abstractPurpose: In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published consensus standardized guidelines for sequence-level variant classification in Mendelian disorders. To increase accuracy and consistency, the Clinical Genome Resource Familial Hypercholesterolemia (FH) Variant Curation Expert Panel was tasked with optimizing the existing ACMG/AMP framework for disease-specific classification in FH. In this study, we provide consensus recommendations for the most common FH-associated gene, LDLR, where >2300 unique FH-associated variants have been identified. Methods: The multidisciplinary FH Variant Curation Expert Panel met in person and through frequent emails and conference calls to develop LDLR-specific modifications of ACMG/AMP guidelines. Through iteration, pilot testing, debate, and commentary, consensus among experts was reached. Results: The consensus LDLR variant modifications to existing ACMG/AMP guidelines include (1) alteration of population frequency thresholds, (2) delineation of loss-of-function variant types, (3) functional study criteria specifications, (4) cosegregation criteria specifications, and (5) specific use and thresholds for in silico prediction tools, among others. Conclusion: Establishment of these guidelines as the new standard in the clinical laboratory setting will result in a more evidence-based, harmonized method for LDLR variant classification worldwide, thereby improving the care of patients with FH.pt_PT
dc.description.sponsorshipClinical Genome Resource (ClinGen) is primarily funded by the National Human Genome Research Institute through the following 3 grants: U41HG006834, U41HG009649, and U41HG009650. ClinGen also receives support for content curation from the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the following 3 grants: U24HD093483, U24HD093486, and U24HD093487. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. J.R.C. acknowledges her PhD fellowship funded by the Science and Technology Foundation (SFRH/BD/108503/2015). L.T. and T.F. are supported by the Ministry of Health of the Czech Republic (grant NU20-02-00261). S.E.H. is an Emeritus British Heart Foundation Professor and is funded by PG08/ 008 and by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. M.T. is supported by a Vanier Canada Graduate Scholarship. L.R.B. is a Michael Smith Foundation for Health Research scholar and a Canada Research Chair in Precision Cardiovascular Disease Prevention. R.A.H. is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Canada Research Chair in Human Genetics, the Martha G. Blackburn Chair in Cardiovascular Research, and operating grants from the Canadian Institutes of Health Research (Foundation Grant) and the Heart and Stroke Foundation of Ontario (G-18- 0022147). J.W.K. is supported by the National Institutes of Health through grants P30DK116074 (to the Stanford Diabetes Research Center), R01 DK116750, R01 DK120565, and R01 DK106236 and by the American Diabetes Association (grant #1-19-JDF-108).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationGenet Med. 2022 Feb;24(2):293-306. doi: 10.1016/j.gim.2021.09.012. Epub 2021 Nov 30pt_PT
dc.identifier.doi10.1016/j.gim.2021.09.012pt_PT
dc.identifier.issn1098-3600
dc.identifier.urihttp://hdl.handle.net/10400.18/8289
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevier/ American College of Medical Genetics and Genomicspt_PT
dc.relationPharmacogenetics of cardiovascular drugs – a step towards personalized medicine
dc.relation.publisherversionhttps://www.sciencedirect.com/science/article/abs/pii/S109836002104140X?via%3Dihubpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subjectACMG/AMPpt_PT
dc.subjectClinGenpt_PT
dc.subjectFamilial Hypercholesterolemiapt_PT
dc.subjectLDLRpt_PT
dc.subjectVariant Classificationpt_PT
dc.subjectDoenças Cardio e Cérebro-vascularespt_PT
dc.subjectColesterolpt_PT
dc.subjectHipercolesterolemia Familiarpt_PT
dc.titleThe Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classificationpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitlePharmacogenetics of cardiovascular drugs – a step towards personalized medicine
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F108503%2F2015/PT
oaire.citation.endPage306pt_PT
oaire.citation.issue2pt_PT
oaire.citation.startPage293pt_PT
oaire.citation.titleGenetics in Medicinept_PT
oaire.citation.volume24pt_PT
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsembargoedAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublicationc0cdd111-f3bc-4210-a1bd-add720c07a1f
relation.isProjectOfPublication.latestForDiscoveryc0cdd111-f3bc-4210-a1bd-add720c07a1f

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