Background and Aims:
The general ACMG/AMP guidelines for standardized variant interpretation in Mendelian disorders are a great asset in determining variants’ pathogenicity, but need to be adapted to each specific gene and disease.
Methods:
In 2016, the Clinical Genome Resource consortium (ClinGen) familial hypercholesterolemia variant curation expert panel (FH-VCEP) was created with the goal to specify the guidelines for LDLR, APOB and PCSK9 in FH. The panel of international FH experts proposed and voted on a draft of specifications, which were tested on known variants. Final adjustments were made based on the pilot study data.
Results
Here we present the final FH-VCEP proposed guidelines for standardized FH variant interpretation, although some criteria are still under discussion. After debating the pilot study results and the three genes different characteristics, it was decided to focus the full FH-specific guidelines on LDLR alone and set some recommendations on how to interpret APOB and PCSK9 variants.
For the LDLR-specific guidelines, five criteria were divided into different levels of evidence, namely functional data (PS3/BS3), segregation (PP1) and cases prevalence criteria (PS4), as well as the ACMG/AMP refinement of PVS1 for loss of function variants. Specific FH allele frequencies were given for population frequency data (PM2/BA1/BS1), hot spot location was defined (PM1) and stipulations were made for cis/trans variant identification (PM3/BP2). Seven criteria were deemed not applicable for LDLR (PP5/BP6/BP7/BP3/PP2/BP1/BP5) and the remaining were kept with minor recommendations.
Conclusions:
After ClinGen approval of these final guidelines, the FH-VCEP will curate all FH variants in ClinVar at a 3-star level, contributing to standardized FH diagnosis worldwide and ultimately improve patient management and prognosis.

06 - SPECIFICATION OF ACMG/AMP GUIDELINES FOR VARIANT INTERPRETATION IN FAMILIAL HYPERCHOLESTEROLEMIA