ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.6491G>A (p.Cys2164Tyr)

dbSNP: rs1555395189
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000659565 SCV000781399 uncertain significance Marfan syndrome 2016-11-01 criteria provided, single submitter clinical testing
Invitae RCV003767911 SCV004570921 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2023-12-31 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 2164 of the FBN1 protein (p.Cys2164Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 27906200; Invitae). ClinVar contains an entry for this variant (Variation ID: 547340). 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 with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic.
Center for Medical Genetics Ghent, University of Ghent RCV000659565 SCV000787235 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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