Submissions for variant NM_001999.4(FBN2):c.905G>C (p.Arg302Thr)

dbSNP: rs863223616

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199256	SCV000250320	uncertain significance	not provided	2014-10-03	criteria provided, single submitter	clinical testing	p.Arg302Thr (AGA>ACA): c.905 G>C in exon 7 of the FBN2 gene (NM_001999.3) The R302T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R302T 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 R302T variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. No missense mutations in nearby residues have been reported in association with contractural arachnodactyly, suggesting 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 TAAD
Invitae	RCV003640876	SCV004478653	uncertain significance	Congenital contractural arachnodactyly	2023-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 302 of the FBN2 protein (p.Arg302Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FBN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 213435). 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.