ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.1651A>G (p.Asn551Asp) (rs138389072)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000433947 SCV000536413 uncertain significance not provided 2017-01-18 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FBN2 gene. The N551D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed at a significant frequency 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 N551D 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 that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, although the N551D variant occurs within 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 congenital arachnodactyly (Collod-Beroud et al., 2003; Frédéric et al., 2009). Furthermore, to our knowledge no studies have been performed to determine the functional effect of the N551D variant.
Ambry Genetics RCV000621468 SCV000738957 uncertain significance Cardiovascular phenotype 2016-02-15 criteria provided, single submitter clinical testing The p.N551D variant (also known as c.1651A>G), located in coding exon 12 of the FBN2 gene, results from an A to G substitution at nucleotide position 1651. The asparagine at codon 551 is replaced by aspartic acid, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs138389072. Based on data fromExAC, the G allele was reported in 2 of121108(0.001%) total alleles (Exome Aggregation Consortium (ExAC), Cambridge, MA (URL: http://exac.broadinstitute.org) [Accessed February 15, 2016]).Based on data from the NHLBI Exome Sequencing Project (ESP), the G allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied, having been observed in 0.02% (1/4406) African American alleles. This amino acid position is highly conserved in available 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 variant remains unclear.

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