ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.7994A>G (p.Asn2665Ser) (rs763173031)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000757272 SCV000233925 uncertain significance not provided 2017-08-22 criteria provided, single submitter clinical testing The N2665S variant has not been published as a mutation or reported as a benign polymorphism to our knowledge. The N2665S 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. Although the N2665S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties; the N2665 residue is conserved across species. In silico analysis predicts this variant is possibly damaging to the protein structure/function. Missense mutations in nearby residues (Y2661C, C2663S, G2668C, G2668D, G2669V) have been reported in HGMD in association with Marfan syndrome and TAAD, supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Invitae RCV000533304 SCV000628000 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2019-01-26 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 2665 of the FBN1 protein (p.Asn2665Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs763173031, ExAC 0.001%). This variant has not been reported in the literature in individuals with FBN1-related conditions. 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 C0). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757272 SCV000885428 likely pathogenic not provided 2017-08-03 criteria provided, single submitter clinical testing
Color Health, Inc RCV001178819 SCV001343353 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2019-02-08 criteria provided, single submitter clinical testing

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