Submissions for variant NM_000138.5(FBN1):c.4243T>C (p.Cys1415Arg)

dbSNP: rs1555397557

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002314309	SCV000738779	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-11-16	criteria provided, single submitter	clinical testing	The p.C1415R variant (also known as c.4243T>C), located in coding exon 34 of the FBN1 gene, results from a T to C substitution at nucleotide position 4243. The cysteine at codon 1415 is replaced by arginine, an amino acid with highly dissimilar properties. This variant has been observed in at least one individual with a personal and/or family history that is consistent with Marfan syndrome (Ambry internal data). The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the cbEGF20 domain (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814198	SCV001755156	likely pathogenic	Abnormality of connective tissue	2021-07-10	criteria provided, single submitter	clinical testing
Center for Medical Genetics Ghent, University of Ghent	RCV000663702	SCV000787036	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing