ClinVar Miner

Submissions for variant NM_174936.3(PCSK9):c.1120G>T (p.Asp374Tyr) (rs137852912)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000505195 SCV000599430 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
Robarts Research Institute,Western University RCV000505195 SCV000782972 pathogenic Familial hypercholesterolemia 1 2018-01-02 criteria provided, single submitter clinical testing
OMIM RCV000003009 SCV000023167 pathogenic Familial hypercholesterolemia 3 2008-02-12 no assertion criteria provided literature only
GeneReviews RCV000003009 SCV000490156 pathogenic Familial hypercholesterolemia 3 2016-12-08 no assertion criteria provided literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000505195 SCV000606699 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Broad Institute Rare Disease Group, Broad Institute RCV000003009 SCV001422592 pathogenic Familial hypercholesterolemia 3 2020-01-22 no assertion criteria provided curation The p.Asp374Tyr variant in PCSK9 has been reported in at least 10 families with hypercholesterolemia, segregated with disease in 20 affected relatives from 5 families, and was absent from large population studies. This variant has also been reported in ClinVar (VariationID: 2875) as likely pathogenic by the Instituto Nacional de Saude Doutor Ricardo Jorge and as pathogenic by Roberts Research Institute, Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, OMIM, and GeneReviews. In vitro functional studies demonstrating that cells transfected with the variant result in a near complete disappearance of LDLR protein provide some evidence that the p.Asp374Tyr variant may impact protein function (PMID: 19081568, 15772090). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Asp374His, has been reported in association with disease in the literature and ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 19081568, 26374825/Variation ID: 265939). The p.Asp374Tyr variant is located in a region of PCSK9 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 19081568). In summary, this variant meets criteria to be classified as pathogenic for hypercholesterolemia in an autosomal dominant manner based on the increased prevalence and cosegregation of the variant in affected individuals compared to controls, in vitro functional studies, and computational evidence. ACMG/AMP Criteria applied: PP1_strong, PM2, PS4_moderate, PP3, PM5_supporting, PS3_supporting, PM1_supporting (Richards 2015).

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