ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.2248T>C (p.Cys750Arg)

dbSNP: rs1555399368
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000800470 SCV000940188 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2019-03-04 criteria provided, single submitter clinical testing This variant has been observed in an individual affected with Marfan syndrome (PMID: 27906200). ClinVar contains an entry for this variant (Variation ID: 492826). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys750 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 27906200, 19293843, 8004112), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 750 of the FBN1 protein (p.Cys750Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine.
Department of Vascular Biology, Beijing Anzhen Hospital RCV001374794 SCV001439559 likely pathogenic Isolated thoracic aortic aneurysm 2018-09-01 criteria provided, single submitter research
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital RCV000582885 SCV000692222 likely pathogenic Marfan syndrome 2014-07-02 no assertion criteria provided clinical testing

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