Submissions for variant NM_000138.5(FBN1):c.2723G>A (p.Cys908Tyr)

dbSNP: rs1057523406

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002314328	SCV000738832	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2016-08-23	criteria provided, single submitter	clinical testing	The p.C908Y pathogenic mutation (also known as c.2723G>A), located in coding exon 22 of the FBN1 gene, results from a G to A substitution at nucleotide position 2723. The cysteine at codon 908 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the hybrid motif #02 domain. This alteration was shown to segregate with Marfan syndrome (MFS) in several members of a family. The proband, who was reported to also have MFS, did not carry this alteration, but the clinical diagnosis was described as debatable (Judge DP et al. Am J Med Genet. 2001;99:39-47). This alteration has also been reported in individuals with ectopia lentis or thoracic aortic aneurysm and dissection (Li D et al. Genet Test. 2008;12:325-30; Wang WJ et al. J Mol Med. 2013;91:37-47). Alterations at the same amino acid position, C905G and C908R, have also been detected in patients with MFS (Haine E et al. J Bone Miner Res. 2015;30:1369-76; Katzke S et al. Hum Mutat. 2002;20:197-208; Stheneur C et al. Eur J Hum Genet. 2009;17:1121-8). 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). And internal structural analysis indicates that p.C908Y eliminates a conserved disulfide motif in TB-hybrid domain 2 of fibrillin-1, which is expected to result in a more dynamic structure in this part of the protein (Jensen SA et al. Structure. 2009;17:759-68). Based on the available evidence, C908Y is classified as a pathogenic mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780256	SCV000917366	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2018-09-05	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.2723G>A (p.Cys908Tyr) results in a non-conservative amino acid change located to the second hybrid motif (Li 2008) in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246192 control chromosomes (gnomAD and publication data). The variant, c.2723G>A, has been reported in the literature in multiple individuals affected with Marfan Syndrome (Judge 2001, Li 2008). The variant was shown to segregate with the disease in these two families, with all the patients having somewhat atypical (i.e. mild to moderate) features. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001093337	SCV001250265	pathogenic	not provided	2019-02-01	criteria provided, single submitter	clinical testing
Department of Vascular Biology, Beijing Anzhen Hospital	RCV001374786	SCV001439551	likely pathogenic	Isolated thoracic aortic aneurysm	2018-09-01	criteria provided, single submitter	research