ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.1537T>C (p.Cys513Arg)

dbSNP: rs1555400279
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000769653 SCV000901056 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2019-12-10 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003767927 SCV004597324 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2023-06-20 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 513 of the FBN1 protein (p.Cys513Arg). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p. Cys513 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 27906200; Invitae), which suggests that this may be a clinically significant amino acid residue. 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: 549022). This variant has not been reported in the literature in individuals affected with FBN1-related conditions.
Center for Medical Genetics Ghent, University of Ghent RCV000663466 SCV000786761 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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