ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.5423-4G>A (rs377036485)

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Total submissions: 6
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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 2020-11-25 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 RCV000617244 SCV000738789 likely benign Cardiovascular phenotype 2019-07-28 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Color Health, Inc RCV001186933 SCV001353545 benign Familial thoracic aortic aneurysm and aortic dissection 2018-12-31 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000277311 SCV001422579 likely benign not specified 2020-01-22 no assertion criteria provided 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,; 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).

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