Submissions for variant NM_000138.5(FBN1):c.5423-4G>A

gnomAD frequency: 0.00026  dbSNP: rs377036485

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001089035	SCV000283637	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-04	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000726081	SCV000341793	uncertain significance	not provided	2016-05-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000277311	SCV000522931	likely benign	not specified	2017-03-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV001186933	SCV000738789	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-07-28	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.
Color Diagnostics, LLC DBA Color Health	RCV001186933	SCV001353545	benign	Familial thoracic aortic aneurysm and aortic dissection	2018-12-31	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000277311	SCV001422579	likely benign	not specified	2020-01-22	criteria provided, single submitter	curation	The c.5423-4G>A variant in FBN1 has not been previously reported in individuals with Marfan Syndrome but has been reported as likely benign and a VUS in ClinVar (Variation ID: 237098). This variant has been identified in 0.1162% (29/24966) of African chromosomes, 0.008469% (3/35424) of Latino chromosomes, and 0.0007757% (1/128922) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs377036485). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The number of missense variants reported in FBN1 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4, BP7, PP2 (Richards 2015).
PreventionGenetics, part of Exact Sciences	RCV004541367	SCV004767675	likely benign	FBN1-related disorder	2019-04-01	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).