Submissions for variant NM_001999.4(FBN2):c.4884A>C (p.Glu1628Asp)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002340493	SCV002635672	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-02-24	criteria provided, single submitter	clinical testing	The p.E1628D variant (also known as c.4884A>C), located in coding exon 38 of the FBN2 gene, results from an A to C substitution at nucleotide position 4884. The glutamic acid at codon 1628 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, aspartic acid is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV003317596	SCV004021583	uncertain significance	not provided	2023-07-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV003775987	SCV004616209	uncertain significance	Congenital contractural arachnodactyly	2022-12-02	criteria provided, single submitter	clinical testing	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. 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. This variant has not been reported in the literature in individuals affected with FBN2-related conditions. This variant is present in population databases (rs371650846, gnomAD 0.004%). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1628 of the FBN2 protein (p.Glu1628Asp).