Submissions for variant NM_001999.4(FBN2):c.5427T>G (p.Ile1809Met)

dbSNP: rs756365546

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200052	SCV000250223	uncertain significance	not provided	2015-07-01	criteria provided, single submitter	clinical testing	p.Ile1809Met (I1809M) (ATT>ATG): c.5427 T>G in exon 43 of the FBN2 gene (NM_001999.3) The I1809M variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The I1809M 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. Additionally, this substitution occurs at a position that is conserved across species. However, the I1809M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The I1809M variant does not affect a Cysteine residue within a calcium-binding EGF-like domain of the FBN2. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with congenital arachnodactyly (Collod-Beroud et al., 2003). Furthermore, missense mutations in nearby residues have not been reported, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAADV2-PANCARD