ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.6446A>G (p.Tyr2149Cys) (rs113080385)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618707 SCV000738870 likely pathogenic Cardiovascular phenotype 2017-02-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000631937 SCV000753040 likely pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2017-08-28 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 2149 of the FBN1 protein (p.Tyr2149Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Marfan syndrome (PMID: 24793577) and in an individual with suspected Marfan syndrome or an aortic phenotype (PMID: 27611364). ClinVar contains an entry for this variant (Variation ID: 42402). This variant generates a cysteine residue in an epidermal-growth-factor (EGF)–like domain of the FBN1 protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for FBN1 protein structure and stability (PMID: 4750422, 16677079). Cysteine creating variants in these domains have been shown to affect protein stability and are overrepresented among individuals with Marfan syndrome (PMID: 15161917, 16571647, 17701892). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035244 SCV000058890 uncertain significance not specified 2009-09-30 criteria provided, single submitter clinical testing

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