Submissions for variant NM_000138.5(FBN1):c.5015G>A (p.Cys1672Tyr)

dbSNP: rs140627

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181694	SCV000233997	pathogenic	not provided	2014-09-02	criteria provided, single submitter	clinical testing	p.Cys1672Tyr (TGT>TAT): c.5015 G>A in exon 41 of the FBN1 gene (NM_000138.4) The C1672Y mutation in the FBN1 gene was previously reported in one Italian individual diagnosed with Marfan syndrome whose clinical features included: abnormal upper to lower segment and increased arm span, pectus carinatum, wrist and thumb sign, reduced elbow extension and MVP (Attanasio et al., 2008). C1672Y results in a non-conservative amino acid substitution resulting in a loss of a Cysteine residue, which may impact disulfide bonding, at a position that is conserved across species. Mutations in the same residue (C1672F, C1672S, C1672R) and in nearby residues (C1663R, C1663Y, C1674G, C1674Y) have been reported in association with Marfan syndrome, further supporting the functional importance of this residue and region of the protein. Furthermore, the C1672Y mutation 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, C1672Y in the FBN1 gene is interpreted as a disease-causing mutation. The variant is found in TAAD panel(s).
Blueprint Genetics	RCV000181694	SCV000928105	likely pathogenic	not provided	2018-12-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336449	SCV002640830	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2020-11-10	criteria provided, single submitter	clinical testing	The p.C1672Y variant (also known as c.5015G>A), located in coding exon 40 of the FBN1 gene, results from a G to A substitution at nucleotide position 5015. The cysteine at codon 1672 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #24 domain. 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). Based on internal structural assessment, this alteration eliminates a structurally critical disulfide in the structurally sensitive cbEGF-like domain #24. This variant has been detected in an individual with systemic features of Marfan syndrome (MFS) (Attanasio M et al. Clin Genet, 2008 Jul;74:39-46). Two other alterations at the same codon, p.C1672R (c.5014T>C) and p.C1672F (c.5015G>T), have been described in association with with MFS, MFS-related features or in MFS cohorts (Schrijver I et al. Am. J. Hum. Genet., 1999; Attanasio M et al. Clin. Genet., 2008 Jul;74:39-46). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.