ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2261A>G (p.Tyr754Cys) (rs137854479)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Medical Genetics Ghent,University of Ghent RCV000017923 SCV000786833 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587806 SCV000695484 pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2016-06-01 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.2261A>G (p.Tyr754Cys) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant affects a conserved tyrosine that is involved in the interaction between adjacent EGF domains. It also introduces a seventh cysteine into exon 18 and is predicted to have a major effect on the structure of the protein. These predictions were confirmed by immunohistochemical staining of fibrillin in fibroblast culture from affected carriers which showed limited amount of fibrillin in the extracellular matrix in addition to disorganized and clumped appearance rather than fibrous structure. This variant is absent from 121586 control chromosomes. This variant has been reported in multiple affected families with MFS and FEL and was shown to co-segregate with disease. Taken together, the variant was classified as "Pathogenic".
OMIM RCV000017923 SCV000038202 pathogenic Marfan syndrome 2004-01-01 no assertion criteria provided literature only

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