ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.6947G>T (p.Cys2316Phe)

dbSNP: rs1555394629
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003767935 SCV004578505 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2023-12-05 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 2316 of the FBN1 protein (p.Cys2316Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 31163209). ClinVar contains an entry for this variant (Variation ID: 549379). 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 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.Cys2316 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 19293843, 35058154), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Center for Medical Genetics Ghent, University of Ghent RCV000663915 SCV000787283 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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