Details

Autor(en) / Beteiligte

• Chora, Joana R.
• Iacocca, Michael A.
• Tichý, Lukáš
• Wand, Hannah
• Kurtz, C. Lisa
• Zimmermann, Heather
• Leon, Annette
• Williams, Maggie
• Humphries, Steve E.
• Hooper, Amanda J.
• Trinder, Mark
• Brunham, Liam R.
• Costa Pereira, Alexandre
• Jannes, Cinthia E.
• Chen, Margaret
• Chonis, Jessica
• Wang, Jian
• Kim, Serra
• Johnston, Tami
• Soucek, Premysl
• Kramarek, Michal
• Leigh, Sarah E.
• Carrié, Alain
• Sijbrands, Eric J.
• Hegele, Robert A.
• Freiberger, Tomáš
• Knowles, Joshua W.
• Bourbon, Mafalda

Titel

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

Ist Teil von

• Genetics in medicine, 2022-02, Vol.24 (2), p.293-306

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2022

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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. 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. 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.