Submissions for variant NM_000138.5(FBN1):c.3904_3915del (p.Ser1302_Cys1305del)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002872688	SCV003238006	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-10-03	criteria provided, single submitter	clinical testing	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). 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 a region of the FBN1 protein in which other variant(s) (p.Cys1305Tyr) have been observed in individuals with FBN1-related conditions (PMID: 29768367). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with FBN1-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.3904_3915del, results in the deletion of 4 amino acid(s) of the FBN1 protein (p.Ser1302_Cys1305del), but otherwise preserves the integrity of the reading frame.