Resolving conflicting LDLR variants in ClinVar - Progress of the ClinGen familial hypercholesterolemia variant curation expert panel

Chora, J.; Iacocca, M.; Elnagheeb, M.; Kullo, I.; Bourbon, M.; on behalf of the ClinGen FH VCEP

Publication

Resolving conflicting LDLR variants in ClinVar - Progress of the ClinGen familial hypercholesterolemia variant curation expert panel

2023-05Conference object

dc.contributor.author	Chora, J.
dc.contributor.author	Iacocca, M.
dc.contributor.author	Elnagheeb, M.
dc.contributor.author	Kullo, I.
dc.contributor.author	Bourbon, M.
dc.contributor.author	on behalf of the ClinGen FH VCEP
dc.date.accessioned	2024-01-24T14:34:27Z
dc.date.available	2024-01-24T14:34:27Z
dc.date.issued	2023-05
dc.description	Abstract publicado em: https://doi.org/10.1016/j.atherosclerosis.2023.06.716	pt_PT
dc.description.abstract	Familial hypercholesterolemia (FH) is the most common monogenic disorder of lipid metabolism. Genetic testing can confirm the clinical diagnosis, but there are currently over 3300 different variants in LDLR deposited in ClinVar and ~400 had conflicting classifications of pathogenicity. Here, we present the progress of LDLR variant classification by the FH Variant Curation Expert Panel (VCEP), composed of 13 reviewers, 17 curators, and 12 associated labs, with our LDLR consensus variant classification guidelines. Variants with conflicting classifications and other variants in the same codon (required to properly classify conflicting variants) are prioritized. Associated labs send internal variant case-level data, which is uploaded into the Variant Curation Interface (VCI) and supplemented by literature evidence. Each variant is assessed by one (very experienced) or two curators and approved by three reviewers before being officially published to ClinVar. As of December 2022, we have completed classification of 316 LDLR variants. Of those with prior conflicting classifications (n=165), 33% were classified as Pathogenic/Likely pathogenic (P/LP), 9% as Benign/Likely benign (B/LB), 55% as Variant of Uncertain Significance (VUS) by insufficient evidence and only 3% remained conflicting. Of the remaining 135 variants, 53% were classified as P/LP, 2% as B/LB and 45% as VUS. Until May 2023, we will evaluate 451 LDLR variants, 247 of them with prior conflicting classifications. Ultimately, efforts of the FH VCEP are aimed at improving FH genetic diagnosis, which relies on accurate LDLR variant classification. FH VCEP’s guidelines significantly decrease conflicting classifications, which will be especially helpful to the FH community.	pt_PT
dc.description.version	N/A	pt_PT
dc.identifier.uri	http://hdl.handle.net/10400.18/8965
dc.language.iso	eng	pt_PT
dc.peerreviewed	no	pt_PT
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/4.0/	pt_PT
dc.subject	Familial Hypercholesterolemia	pt_PT
dc.subject	Variant Curation	pt_PT
dc.subject	Variant Classification	pt_PT
dc.subject	ClinGen	pt_PT
dc.subject	Doenças Cardio e Cérebro-vasculares	pt_PT
dc.title	Resolving conflicting LDLR variants in ClinVar - Progress of the ClinGen familial hypercholesterolemia variant curation expert panel	pt_PT
dc.type	conference object
dspace.entity.type	Publication
oaire.citation.conferencePlace	Mannheim, Germany	pt_PT
oaire.citation.title	91st EAS Congress - Atherosclerosis, 21-24 may 2023	pt_PT
rcaap.rights	restrictedAccess	pt_PT
rcaap.type	conferenceObject	pt_PT