Submissions for variant NM_000138.5(FBN1):c.2639G>A (p.Gly880Asp)

dbSNP: rs886038953

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002310868	SCV000319317	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2014-08-08	criteria provided, single submitter	clinical testing	The p.G880D variant (also known as c.2639G>A), located in coding exon 21 of the FBN1 gene, results from a G to A substitution at nucleotide position 2639. The glycine at codon 880 is replaced by aspartic acid, an amino acid with some similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6,493 samples (12,986 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Two other alterations of the same codon in the hybrid motif #02 domain, p.G880S (c.2638G>A) and p.G880R (c.2638G>C), have been reported. The recurrent p.G880S (c.2638G>A) mutation was detected in multiple patients with classic Marfan syndrome (Rommel K et al. Hum Mutat. 2002; 20(5):406-7; Attanasio M et al. Clin Genet. 2008; 74(1):39-46). Based on the majority of available evidence to date, the p.G880D variant is likely to be pathogenic.
GeneDx	RCV000418771	SCV000531385	likely pathogenic	not provided	2016-09-01	criteria provided, single submitter	clinical testing	The G880D likely pathogenic variant in the FBN1 gene has not been published as a pathogenic or benign variant to our knowledge. This variant 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. The G880D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution also occurs at a position that is conserved across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, a missense variant in the same residue (G880S) has been reported in the Human Gene Mutation Database in association with Marfan syndrome (Stenson et al., 2014), supporting the functional importance of this residue of the protein. Nevertheless, the G880D variantdoes not affect a Cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003). Therefore, the G880D variant in the FBN1 gene is likely pathogenic.
Department of Vascular Biology, Beijing Anzhen Hospital	RCV001374788	SCV001439553	uncertain significance	Isolated thoracic aortic aneurysm	2018-09-01	criteria provided, single submitter	research