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Development of Gene-Specific ACMG/AMP Guidelines for the Interpretation of APOB and PCSK9 Variants in Familial Hypercholesterolemia

2025-05-04Documento de conferência Acesso restrito
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dc.contributor.authorChora, Joana Rita
dc.contributor.authorHooper, Amanda
dc.contributor.authorGutierrez-Ford, Christina
dc.contributor.authorKullo, Iftikhar
dc.contributor.authorBourbon, Mafalda
dc.contributor.authoron behalf of the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
dc.date.accessioned2026-03-04T16:02:25Z
dc.date.available2026-03-04T16:02:25Z
dc.date.issued2025-05-04
dc.description.abstractBackground and Aims: The general ACMG/AMP guidelines for standardized variant interpretation provide a critical framework for determining pathogenicity but require adaptation to specific genes and diseases. While LDLR-specific guidelines for familial hypercholesterolemia (FH) have been in use since 2020, similar adaptations for APOB and PCSK9 are needed to address the unique characteristics of these genes in FH diagnosis. Methods: The Clinical Genome Resource (ClinGen) consortium’s FH variant curation expert panel (FH VCEP) expanded its efforts to develop tailored guidelines for APOB and PCSK9. A panel of international FH experts proposed and voted on specifications for these genes, based on current evidence. These adaptations were compared to LDLR-specific criteria for consistency and refined based on gene-specific attributes. Results: The proposed guidelines address the unique features of APOB and PCSK9 variants. For both genes, adaptations included adjustment of thresholds for population frequency criteria (PM2/BA1/BS1), specification of appropriate functional studies (PS3/BS3) to reflect each gene’s role in the LDLR cycle, and documented critical protein regions (PM1). Several criteria were considered to be applicable in the same manner as for LDLR: phenotype specificity (PP4), frequency of cases (PS4), co-segregation data (PP1), and cases with more than onevariant (PM3/BP2). As null variants in APOB and loss-of-function variants in PCSK9 are not mechanisms for FH, the evidence code for truncating variants (PVS1) was deemed not applicable for both genes. Lack of segregation (BS4) in APOB was also deemed not applicable due to documented incomplete penetrance of APOB variants. Conclusions: With the increasing detection of variants through advances in sequencing and genotyping technologies, these guidelines represent a significant step toward standardizing APOB and PCSK9 variant interpretation in FH diagnosis. Following ClinGen approval, these gene-specific recommendations will enable high-confidence classification of APOB and PCSK9 variants in ClinVar, enhancing the accuracy of FH diagnosis and supporting personalized management strategies for patients worldwide.eng
dc.description.sponsorshipWith thanks to the EAS for support under EAS Young Fellows Alumni. The contents of this poster are presented on behalf of the ClinGen FH Variant Curation Committee (https://clinicalgenome.org/affiliation/50004/). JR Chora is funded by the PerMedFH project (LCF/PR/HP23/52330032). PerMedFH project funded by La Caixa Foundation in partnership with FCT.
dc.identifier.urihttp://hdl.handle.net/10400.18/11149
dc.language.isoeng
dc.peerreviewedn/a
dc.rights.uriN/A
dc.subjectFamilial Hypercholesterolemia
dc.subjectGenetic Diagnosis
dc.subjectLDRL
dc.subjectAPOB
dc.subjectPCSK9
dc.subjectDoenças Cardio e Cérebro-vasculares
dc.titleDevelopment of Gene-Specific ACMG/AMP Guidelines for the Interpretation of APOB and PCSK9 Variants in Familial Hypercholesterolemiaeng
dc.typeconference object
dspace.entity.typePublication
oaire.citation.conferenceDate2025-05-04
oaire.citation.conferencePlaceGlasgow, Scotland (UK)
oaire.citation.title93rd European Atherosclerosis Society (EAS) Congress 4-7 may 2025
oaire.versionhttp://purl.org/coar/version/c_b1a7d7d4d402bcce

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