{Reference Type}: Journal Article
{Title}: The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification.
{Author}: Chora JR;Iacocca MA;Tichý L;Wand H;Kurtz CL;Zimmermann H;Leon A;Williams M;Humphries SE;Hooper AJ;Trinder M;Brunham LR;Costa Pereira A;Jannes CE;Chen M;Chonis J;Wang J;Kim S;Johnston T;Soucek P;Kramarek M;Leigh SE;Carrié A;Sijbrands EJ;Hegele RA;Freiberger T;Knowles JW;Bourbon M; ;
{Journal}: Genet Med
{Volume}: 24
{Issue}: 2
{Year}: 02 2022
{Factor}: 8.864
{DOI}: 10.1016/j.gim.2021.09.012
{Abstract}: 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.<BR>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.<BR>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.<BR>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.