Submissions for variant NM_000138.5(FBN1):c.4367G>T (p.Cys1456Phe)

dbSNP: rs397515805

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475879	SCV000544898	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-07-19	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 1456 of the FBN1 protein (p.Cys1456Phe). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys1456 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 19293843, 31098894, 33824467), 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: 406329). This missense change has been observed in individual(s) with clinical features of FBN1-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency).
All of Us Research Program, National Institutes of Health	RCV004801987	SCV005424785	likely pathogenic	Marfan syndrome	2024-08-31	criteria provided, single submitter	clinical testing	The c.4367G>T (p.Cys1456Phe) variant in FBN1 gene that encodes for fibrillin 1, has not been reported in individuals with FBN1-related conditions in the published literature. This variant affects a cysteine residue in the calcium binding EGF-like (cbEGF21) domain (PMID: 12938084, 17627385). Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be critical for FBN1 protein structure (PMID: 16905551, 19349279). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.961). This variant is absent in the general population database gnomAD and interpreted as likely pathogenic by one ClinVar submitter (ClinVar ID: 406329). Other missense variants affecting the same amino acid residue (p.Cys1456Ser, p.Cys1456Tyr, p.Cys1456Gly, p.Cys1456Arg) have been observed in multiple individuals with Marfan syndrome/marfanoid features and classified as likely pathogenic or pathogenic by multiple ClinVar submitters (ClinVar ID: 42360, 42357, 1740052, 982320). Therefore, the c.4367G>T (p.Cys1456Phe) variant in FBN1 gene is classified as likely pathogenic.