Submissions for variant NM_000138.4(FBN1):c.3974A>C (p.Glu1325Ala) (rs794728331)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Human Genetics, Inc	RCV000659535	SCV000781362	likely pathogenic	Marfan syndrome	2016-11-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000181692	SCV000233995	pathogenic	not provided	2014-09-25	criteria provided, single submitter	clinical testing	p.Glu1325Ala (GAA>GCA): c.3974 A>C in exon 33 of the FBN1 gene (NM_000138.4) While the E1325A mutation in the FBN1 gene has not been reported to our knowledge, a mutation affecting this same residue, (E1325Q), has been reported in association with Marfan syndrome (Biggin A et al., 2004). Additionally, mutations in nearby residues (D1322H, D1322G, C1326R, C1333S ) have been reported in association with Marfan syndrome, further supporting the functional importance of this residue and this region of the protein. E1325A, within EGF - like calcium binding domain 22 of FBN1, results in 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. The E1325 residue is highly conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, E1325A 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, E1325A in the FBN1 gene is interpreted as a likely disease-causing mutation. The variant is found in TAAD panel(s).
Invitae	RCV000706621	SCV000835684	uncertain significance	Marfan syndrome; Thoracic aortic aneurysm and aortic dissection	2018-07-02	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with alanine at codon 1325 of the FBN1 protein (p.Glu1325Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with clinical features of Marfan syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 200185). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. The observation of one or more missense substitutions at this codon (p.Glu1325Gln and p.Glu1325Ala) in affected individuals suggests that this may be a clinically significant residue (PMID: 14695540, Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.