ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.4467T>A (p.Asn1489Lys) (rs193922205)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000586485 SCV000058845 uncertain significance not specified 2019-02-11 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855643 SCV000695543 likely pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2019-03-06 criteria provided, single submitter clinical testing Variant summary: FBN1 c.4467T>A (p.Asn1489Lys) results in a non-conservative amino acid change located in the EGF-like calcium-binding and EGF-like domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245886 control chromosomes (gnomAD). c.4467T>A has been reported in the literature in individuals affected with Marfan Syndrome (Baetens_2011, Regalado_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant once as likely pathogenic and once as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV001046640 SCV001210551 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2020-04-15 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 1489 of the FBN1 protein (p.Asn1489Lys). The asparagine residue is moderately conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with thoracic aortic aneurysm and dissection (PMID: 26621581) and has been identified in individuals affected with this condition (PMID: 20082464, Invitae) and Marfan syndrome (PMID: 21542060). ClinVar contains an entry for this variant (Variation ID: 36076). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Center for Medical Genetics Ghent,University of Ghent RCV000029738 SCV000787068 uncertain significance Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
University of Washington Center for Mendelian Genomics, University of Washington RCV000755191 SCV000883020 likely pathogenic Familial thoracic aortic aneurysm; Acute aortic dissection 2016-01-20 no assertion criteria provided research

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