Submissions for variant NM_001999.4(FBN2):c.5568T>A (p.Asn1856Lys)

dbSNP: rs1201284691

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521512	SCV000620683	uncertain significance	not provided	2017-09-08	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the FBN2 gene. The N1856K variant has not been published as pathogenic or been reported as benign to our knowledge. The N1856K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N1856K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to asparagine (N) are tolerated across species. Consequently, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Lastly, although the N1856K variant is within a calcium-binding EGF-like domain of the FBN2 gene, it does not affect a cysteine residue. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN2-related disorders (Frédéric et al., 2009).
Ambry Genetics	RCV003159687	SCV003913583	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-12-15	criteria provided, single submitter	clinical testing	The p.N1856K variant (also known as c.5568T>A), located in coding exon 44 of the FBN2 gene, results from a T to A substitution at nucleotide position 5568. The asparagine at codon 1856 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV003640909	SCV004547175	uncertain significance	Congenital contractural arachnodactyly	2023-08-30	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FBN2 protein function. ClinVar contains an entry for this variant (Variation ID: 451922). This variant has not been reported in the literature in individuals affected with FBN2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1856 of the FBN2 protein (p.Asn1856Lys).