Submissions for variant NM_000138.5(FBN1):c.1664G>T (p.Cys555Phe)

dbSNP: rs794728172

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181437	SCV000233739	pathogenic	not provided	2013-02-28	criteria provided, single submitter	clinical testing	p.Cys555Phe (TGC>TTC): c.1664 G>T in exon 14 of the FBN1 gene (NM_000138.4)While the Cys555Phe mutation in the FBN1 gene has not been reported to our knowledge, a mutation affecting this same codon (Cys555Arg) has been reported in a patient with suspected Marfan syndrome (Waldmuller S et al., 2007). Additionally, mutations in nearby residues (Asn548Ile, Cys557Tyr, Gly560Ser) have been reported in association with Marfan syndrome or fibrillinopathy, further supporting the functional importance of this codon and this region of the protein. Cys555Phe results in a non-conservative amino acid substitution of a neutral, polar Cysteine with a non-polar Phenylalanine at a position that is conserved across species. In silico analysis predicts Cys555Phe is damaging to the protein structure/function. Furthermore, the Cys555Phe variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, Cys555Phe in the FBN1 gene is interpreted as a likely disease-causing mutation. The variant is found in TAAD panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002516835	SCV003331350	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-03-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys555 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 17418587, 32679894; 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: 199974). This missense change has been observed in individual(s) with Marfan syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 555 of the FBN1 protein (p.Cys555Phe).