ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1379G>A (p.Cys460Tyr) (rs1597581001)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000788531 SCV000927680 likely pathogenic not provided 2018-05-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001375613 SCV001572527 uncertain significance not specified 2021-04-15 criteria provided, single submitter clinical testing Variant summary: FBN1 c.1379G>A (p.Cys460Tyr) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251242 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1379G>A has been reported in the literature in at least an individual who was diagnosed with bilateral Ectopia Lentis and mild mitral valve prolapse with normal aortic root but who did not fulfill revised Ghent criteria (Zadeh_2011). This report however, does not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Missense mutations affecting or creating cysteine residues are listed among the criteria for a causal FBN1 mutation when identified as de novo (with proven paternity) in the revised Ghent criteria for the diagnosis of Marfan and related conditions (Loeys BL et al, 2010). One ClinVar submitter (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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