ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.4222T>C (p.Cys1408Arg) (rs397515802)

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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,Partners HealthCare Personalized Medicine RCV000035190 SCV000058832 pathogenic Marfan syndrome 2014-04-18 criteria provided, single submitter clinical testing The Cys1408Arg variant in FBN1 has been previously reported in 4 individuals wit h clinical features of Marfan syndrome, segregated with disease in 5 affected fa mily members from 1 family including 2 obligate carriers, and was absent from la rge population studies (Stheneur 2009, Yoo 2010, LMM unpublished data). The cyst eine (Cys) at position 1408 is highly conserved in mammals and evolutionarily di stant species, supporting that a change at this position may not be tolerated. I n addition, this variant affects a cysteine residue; cysteine substitutions are a common finding in individuals with Marfan syndrome (Schrijver, 1999). In summa ry, this variant meets our criteria to be classified as pathogenic based on the available evidence described above (http://pcpgm.partners.org/LMM).
Invitae RCV000684806 SCV000544828 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-06-12 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 1408 of the FBN1 protein (p.Cys1408Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (rs397515802, ExAC no frequency). This variant has been reported in several individuals affected with Marfan syndrome (PMID: 19293843, 19863550). ClinVar contains an entry for this variant (Variation ID: 42351). This variant affects a cysteine residue located within an epidermal-growth-factor (EGF)–like domain of the FBN1 protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for FBN1 protein structure and stability (PMID: 3495735, 4750422, 16677079). In addition, missense substitutions within the FBN1 EGF-like domains affecting cysteine residues 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 RCV000035190 SCV000787035 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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