Submissions for variant NM_000138.5(FBN1):c.2584T>C (p.Cys862Arg)

dbSNP: rs2043595650

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001063161	SCV001227996	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-09-29	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 862 of the FBN1 protein (p.Cys862Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 8281141). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 857483). 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. For these reasons, this variant has been classified as Pathogenic. 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).
All of Us Research Program, National Institutes of Health	RCV004000132	SCV004830306	pathogenic	Marfan syndrome	2023-08-17	criteria provided, single submitter	clinical testing	This variant was observed to occur de novo in an affected individual and parentage was confirmed (PMID: 8281141). Functional studies suggest that this variant results in a deleterious effect to the protein that is sufficient to be disease-causing (PMID: 16905551, 16905551). This variant has been reported in multiple individuals with Marfan syndrome (PMID: 8281141, 9150726, 31055806). This missense substitution occurs at a Cysteine that is known to be critical to protein structure/function (PMID: 16905551). This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is predicted to be deleterious by in silico analysis.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004000132	SCV004848457	likely pathogenic	Marfan syndrome	2020-08-24	criteria provided, single submitter	clinical testing	The p.Cys862Arg variant in FBN1 has been identified as a de novo variant in 1 individual with Marfan syndrome (Tynan 1993 PubMed: 8281141) and was absent from large population studies. Three additional variants involving this codon (p.Cys862Ser, p.Cys862Trp and p.Cys862Tyr) have been reported (Wang 2019 PMID: 31106028; Takeda 2018 PMID: 29848614). This variant is reported in ClinVar (allele ID: 842502). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Furthermore, this variant affects a highly conserved cysteine residue in the EGF-like domains, which is a common finding in individuals with Marfan syndrome (Schrijver 1999). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PM2; PM1; PM5_Supporting; PS4_Supporting; PM6; PP3.