Specification of ACMG/AMP guidelines for standardized variant interpretation in familial hypercholesterolemia: On behalf of the ClinGen FH Variant Curation Expert Panel

• Abstract
• Webcast

Abstract

Background and Aims

Familial hypercholesterolemia (FH) is a heritable disorder characterized by elevated low-density lipoprotein (LDL) cholesterol levels and premature cardiovascular disease. Increasingly, patients with a clinical suspicion of FH are being offered genetic testing as part of diagnosis. However, determining pathogenicity of identified DNA variants remains a major challenge; this process is often rudimentary and differs among laboratories. To improve accuracy, concordance and standardization, the ClinGen FH Variant Curation Expert Panel (VCEP) has been tasked with developing FH-specific variant interpretation guidelines, derived from American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) recommendations (2015).

Methods

Following review of ACMG/AMP recommendations, the FH VCEP met through frequent emails and conference calls to propose FH-specific modifications. After multiple preliminary iterations, pilot testing, debate and further commentary, consensus among experts was reached.

Results

Here, we present a consensus set of FH-ACMG/AMP guidelines, which focus first on the LDL receptor gene (LDLR), and include: 1) indications for loss-of-function variant types; 2) functional study criteria specifications; 3) alteration of population data frequency thresholds; 4) specific use and thresholds for in silico prediction tools; and 5) co-segregation criteria specifications.

Conclusions

Establishment of these guidelines will help to achieve a more evidence-based, standardized method for the classification of variants detected in FH patients worldwide. Ultimately, all ~3000 FH-associated variants currently deposited in the ClinVar database will be re-classified using the FH-ACMG/AMP criteria, while promoting these guidelines as the new “gold standard” for variant classification among the FH community will ensure novel variants identified in real-time are appropriately evaluated.

Hide

Webcast

[session]

[presentation]

[presenter]

Hide