Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000590273 | SCV000695597 | uncertain significance | not provided | 2017-07-18 | criteria provided, single submitter | clinical testing | Variant summary: The FBN1 c.7383C>G (p.Asn2461Lys) variant located in the EGF-like #38 domain (via InterPro) involves the alteration of a conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome. However, these predictions have yet to be functionally assessed. This variant was found in 1/121314 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic FBN1 variant (0.0001125). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. In addition, the variant does not alter or create a Cysteine, which plays a key role in proper FBN1 protein function. Therefore, because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available. |
| Invitae | RCV000793151 | SCV000932492 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2023-12-19 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 2461 of the FBN1 protein (p.Asn2461Lys). This variant is present in population databases (rs754047254, gnomAD 0.007%). This missense change has been observed in individual(s) with thoracic aortic aneurysm and dissection (Invitae). ClinVar contains an entry for this variant (Variation ID: 495645). 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 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. 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. |
| ARUP Laboratories, |
RCV000590273 | SCV001472854 | likely pathogenic | not provided | 2019-12-07 | criteria provided, single submitter | clinical testing | The FBN1 c.7383C>G; p.Asn2461Lys variant (rs754047254), to our knowledge, is not reported in the medical literature but is reported in the LOVD database (see link). This variant is reported in ClinVar (Variation ID: 495645), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The asparagine at codon 2461 is highly conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, this asparagine residue is located in the conserved residues of an EGF consensus sequence, which is a common mechanism of pathogenicity (Wu 1995). Additionally, other variants at this codon (c.7381A>C; p.Asn2461His; c.7382A>C; p.Asn2461Thr) have been reported in individuals with Marfan syndrome (Franken 2016, Stheneur 2009). Based on available information, this variant is considered to be likely pathogenic. References: Link to LOVD: https://databases.lovd.nl/shared/variants/0000459658#00007761 Franken R et al. Genotype impacts survival in Marfan syndrome. Eur Heart J. 2016 Nov 14;37(43):3285-3290. Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009 Sep;17(9):1121-8. Wu YS et al. Fibrillin domain folding and calcium binding: significance to Marfan syndrome. Chem Biol. 1995 2(2):91-7. |