Submissions for variant NM_000138.5(FBN1):c.5741G>A (p.Cys1914Tyr)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV002294598	SCV002587113	likely pathogenic	Marfan syndrome	2022-10-04	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS4_MOD, PM2_SUP, PM5_SUP, PP2, PP3
Ambry Genetics	RCV002346577	SCV002650690	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2020-02-12	criteria provided, single submitter	clinical testing	The p.C1914Y variant (also known as c.5741G>A), located in coding exon 46 of the FBN1 gene, results from a G to A substitution at nucleotide position 5741. The cysteine at codon 1914 is replaced by tyrosine, an amino acid with highly dissimilar properties. 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). This variant was detected in an individual with features of Marfan syndrome (Ambry internal data). Based on internal structural assessment, this alteration eliminates a structurally critical disulfide in the structurally sensitive cbEGF domain #28. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.