Submissions for variant NM_000138.5(FBN1):c.6697C>T (p.Pro2233Ser)

dbSNP: rs794728255

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181576	SCV000233879	uncertain significance	not provided	2022-12-19	criteria provided, single submitter	clinical testing	Identified in a patient with Marfan syndrome in published literature (Stengl et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33059708)
Invitae	RCV000801586	SCV000941368	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-03-10	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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. This variant disrupts the p.Pro2233 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 24199744; Invitae), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 200091). This missense change has been observed in individual(s) with FBN1-related conditions (PMID: 33059708; Invitae). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2233 of the FBN1 protein (p.Pro2233Ser).
Ambry Genetics	RCV002362929	SCV002663553	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-02-27	criteria provided, single submitter	clinical testing	The alteration results in an amino acid change:_x000D_ _x000D_ The c.6697C>T (p.P2233S) alteration is located in exon 55 (coding exon 54) of the FBN1 gene. This alteration results from a C to T substitution at nucleotide position 6697, causing the proline (P) at amino acid position 2233 to be replaced by a serine (S). The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the FBN1 c.6697C>T alteration was not observed, with coverage at this position. An alteration at the same codon has been observed in affected individuals:_x000D_ Another alteration affecting the same amino acid, p.P2233R (c.698C>G), has been reported in association with Marfan syndrome (Pees, 2014). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.P2233 amino acid is conserved in available vertebrate species. The alteration is predicted deleterious by in silico modeling:_x000D_ _x000D_ The p.P2233S alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Clinical Genetics Laboratory, Region Ostergotland	RCV000663893	SCV003925555	likely pathogenic	Marfan syndrome	2023-04-12	criteria provided, single submitter	clinical testing
Center for Medical Genetics Ghent, University of Ghent	RCV000663893	SCV000787259	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing