ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.5840G>A (p.Cys1947Tyr)

dbSNP: rs397515828
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000035237 SCV000058882 likely pathogenic Marfan syndrome 2009-05-04 criteria provided, single submitter clinical testing
Invitae RCV001384076 SCV001583455 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2022-10-07 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 42395). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 24793577; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1947 of the FBN1 protein (p.Cys1947Tyr).
Centre of Medical Genetics, University of Antwerp RCV000035237 SCV002025364 pathogenic Marfan syndrome 2021-03-01 criteria provided, single submitter research PM2, PVS2, PP4

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