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

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. 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.

The Role of Registers in Increasing Knowledge and Improving Management of Children and Adolescents Affected by Familial Hypercholesterolemia: the LIPIGEN Pediatric Group

“…We defined a subject as “positive” to the genetic analysis if at least one causative variant, pathogenic or likely pathogenic, was detected according to the ACMG Guidelines ( Richards et al, 2015 ) and the more recent FH-specific suggestions ( Chora et al, 2018 ; Chora et al, 2022 ); we defined a subject as “inconclusive” if only variants with uncertain clinical significance (VUS) were identified, and “negative” if only benign/likely benign or no variants in the tested genes were found ( Richards et al, 2015 ; Chora et al, 2022 ) despite the clinical phenotype.…”

Effects of Different Types of Pathogenic Variants on Phenotypes of Familial Hypercholesterolemia

“…Since patients with FH typically do not have tendon xanthomas (one of the most important clinical diagnostic criteria) in childhood, genetic testing is essential for early diagnosis of FH ( Tada et al, 2021d ; Matsunaga et al, 2021 ; Nagahara et al, 2021 ). Furthermore, given the criteria of pathogenicity of genetic variants and the catalog of pathogenic variants of FH, there is a growing demand for further risk stratification of patients with FH based on genotype ( Chora et al, 2022 ). The growing demand is natural in this personalized medicine era, when phenotypes can be estimated using genotypes and the best treatments for many inherited diseases can be determined based on genotype ( Sukrithan et al, 2019 ; Pujol et al, 2021 ; Tada, 2021 ).…”

Harmonizing variant classification for return of results in the All of Us Research Program

“…Application of this line of evidence can be subjective as there is no definitive source of well‐established functional domains, making it difficult to come to consensus when laboratories differ on their definition of a functional domain. Expert defined regions or codons that meet this line of evidence, such as the MYH7 specifications defining the PM1 applicable region as codons 181‐937 or the LDLR specifications selecting 60 highly conserved cysteine residues as qualifying for PM1 criterion, removed the subjectivity in determining when this evidence is applicable and led to concordant reclassifications between laboratories (Chora et al, 2021; Kelly et al, 2018). VCEP specifications will be used throughout AoURP to increase consistency in classifications between CVLs.…”