ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.5950T>C (p.Cys1984Arg)

dbSNP: rs1555395659
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre of Medical Genetics, University of Antwerp RCV000663837 SCV002025373 pathogenic Marfan syndrome 2021-03-01 criteria provided, single submitter research PM2, PVS2, PP4
Labcorp Genetics (formerly Invitae), Labcorp RCV001855420 SCV002238903 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2024-10-28 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 1984 of the FBN1 protein (p.Cys1984Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 21542060). ClinVar contains an entry for this variant (Variation ID: 549320). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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). This variant disrupts the p.Cys1984 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 26787436, 27906200), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV004773080 SCV005384343 likely pathogenic not provided 2024-04-24 criteria provided, single submitter clinical testing Affects a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12938084, 37116669, 34456093, 21542060, 35058154, 27906200)
Center for Medical Genetics Ghent, University of Ghent RCV000663837 SCV000787194 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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