ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.7748A>G (p.Asn2583Ser)

dbSNP: rs2042934435
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001059003 SCV001223606 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2024-09-23 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 2583 of the FBN1 protein (p.Asn2583Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (internal data). ClinVar contains an entry for this variant (Variation ID: 854052). 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) indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. 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.
Ambry Genetics RCV004822301 SCV005585782 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2024-08-30 criteria provided, single submitter clinical testing The p.N2583S variant (also known as c.7748A>G), located in coding exon 62 of the FBN1 gene, results from an A to G substitution at nucleotide position 7748. The asparagine at codon 2583 is replaced by serine, an amino acid with highly similar properties. This variant alters a conserved residue in the calcium-binding consensus sequence of a cbEGF domain and is expected to disrupt FBN1 function (Handford PA et al. Nature. 1991; 351(6322):164-7). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

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