Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002313268 | SCV000738908 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2017-06-16 | criteria provided, single submitter | clinical testing | The p.N2461S variant (also known as c.7382A>G), located in coding exon 59 of the FBN1 gene, results from an A to G substitution at nucleotide position 7382. The asparagine at codon 2461 is replaced by serine, an amino acid with highly similar properties, and is located in the cbEGF-like #38 domain. Other alterations affecting the same amino acid, p.N2461H (c.7381A>C) and p.N2461T (c.7382A>C), have been reported in association with Marfan syndrome (Stheneur C et al. Eur. J. Hum. Genet., 2009 Sep;17:1121-8; Franken R et al. Eur. Heart J., 2016 Nov;37:3285-3290). 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 alteration remains unclear. |
| Labcorp Genetics |
RCV001039062 | SCV001202572 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2025-01-26 | 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 2461 of the FBN1 protein (p.Asn2461Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Marfan syndrome (internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 519781). 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%. This variant disrupts the p.Asn2461 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 19293843, 26787436), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |