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 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2019-04-30 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine with serine at codon 2461 of the FBN1 protein (p.Asn2461Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with clinical features of Marfan syndrome in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 519781). 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: "Tolerated"; 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. 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |