Submissions for variant NM_000138.5(FBN1):c.6698C>T (p.Pro2233Leu)

dbSNP: rs1566894783

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000707547	SCV000836648	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-09-11	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2233 of the FBN1 protein (p.Pro2233Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with FBN1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 583258). 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. This variant disrupts the p.Pro2233 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24199744; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV003318503	SCV003935984	likely pathogenic	Marfan syndrome		criteria provided, single submitter	clinical testing