ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.3634T>C (p.Cys1212Arg)

dbSNP: rs2043497933
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001215434 SCV001387179 likely pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2019-07-31 criteria provided, single submitter clinical testing 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). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been observed in an individual with clinical features of Marfan syndrome (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 1212 of the FBN1 protein (p.Cys1212Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine.

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