Submissions for variant NM_001999.4(FBN2):c.8497C>T (p.Arg2833Cys)

gnomAD frequency: 0.00002  dbSNP: rs863223592

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200436	SCV000250258	uncertain significance	not provided	2017-07-24	criteria provided, single submitter	clinical testing	p.Arg2833Cys (CGT>TGT): c.8497 C>T in exon 65 of the FBN2 gene (NM_001999.3) The R2833C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R2833C 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 R2833C variant is 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 R2833C results in gain of Cysteine residue, which may impact disulfide bonding. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, no missense mutations in nearby residues have been reported in association with TAAD/ Marfan syndrome, indicating this region of the protein may tolerate 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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001054165	SCV001218467	uncertain significance	Congenital contractural arachnodactyly	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2833 of the FBN2 protein (p.Arg2833Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 213374). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.