Submissions for variant NM_001999.4(FBN2):c.4594G>A (p.Asp1532Asn) (rs863223574)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197040	SCV000250213	likely pathogenic	not provided	2014-07-10	criteria provided, single submitter	clinical testing	p.Asp1532Asn (GAT>AAT): c.4594 G>A in exon 35 of the FBN2 gene (NM_001999.3) The D1532N variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The D1532N 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 D1532N variant, which occurs in the calcium binding EGF-like domain, 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 that is conserved across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, D1532N alters the last base of exon 35, immediately 5' of the cononical GT" splice donor site. In silico analysis with 2 different splice algorithms predicts this mutation severely alters the donor site at the exon 35/intron 35 junction of the FBN2 gene and is expected to cause abnormal gene splicing. This may lead to protein truncation or absence of protein due to mRNA decay. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. This variant was found in TAAD"
Invitae	RCV001220936	SCV001392950	uncertain significance	Congenital contractural arachnodactyly	2019-04-08	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with asparagine at codon 1532 of the FBN2 protein (p.Asp1532Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant also falls at the last nucleotide of exon 35 of the FBN2 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FBN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 213330). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.