Submissions for variant NM_000138.5(FBN1):c.1345G>A (p.Val449Ile)

gnomAD frequency: 0.00009  dbSNP: rs139058991

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER _CC_NCGL, University of Washington	RCV000148499	SCV000190208	uncertain significance	Marfan syndrome	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455446	SCV000539150	uncertain significance	not specified	2016-04-25	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband, no segs; ExAC: 1/8604 East Asian chromosomes
Color Diagnostics, LLC DBA Color Health	RCV000771785	SCV000904469	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-07-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001071912	SCV001237244	benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-24	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771785	SCV001332891	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2018-03-27	criteria provided, single submitter	clinical testing
GeneDx	RCV003328558	SCV004035659	uncertain significance	not provided	2023-09-15	criteria provided, single submitter	clinical testing	Identified in a patient with dilated aortic root and tall stature; however, this individual did not have a typical Marfanoid appearance or ocular symptoms, did not meet diagnostic criteria for Marfan syndrome, and segregation studies to investigate whether the variant was present in the father with mitral valve insufficiency were not performed (Rommel et al., 2002); In silico analysis supports that this missense variant does not alter protein structure/function; 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 vitro functional study suggests that variant p.V449I may affect FBN1 binding affinity; however, since experiments were conducted using FBN1 fragments rather than full-length FBN1, additional studies required (Chaudry et al., 2007); This variant is associated with the following publications: (PMID: 25652356, 24941995, 25812041, 25637381, 12402346, 17242066, 31211626)
Ambry Genetics	RCV000771785	SCV005113146	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2024-04-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.