ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.5834A>G (p.Asn1945Ser)

gnomAD frequency: 0.00001  dbSNP: rs863223578
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002311055 SCV000320435 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2015-11-13 criteria provided, single submitter clinical testing The p.N1945S variant (also known as c.5834A>G), located in coding exon 46 of the FBN2 gene, results from an A to G substitution at nucleotide position 5834. The asparagine at codon 1945 is replaced by serine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Invitae RCV003525875 SCV004271370 uncertain significance Congenital contractural arachnodactyly 2023-11-13 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1945 of the FBN2 protein (p.Asn1945Ser). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 213341). 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 expected to disrupt FBN2 protein function with a positive predictive value of 80%. 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.

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