ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.7016G>A (p.Cys2339Tyr) (rs1555394580)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000590370 SCV000695594 uncertain significance not provided 2017-02-17 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.7016G>A (p.Cys2339Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index) although these predictions have yet to be functionally assessed. This variant is absent in 119,502 control chromosomes. The variant of interest lies in a conserved region within a TGF-beta binding (TB) domain. Many manifestations of Marfan syndrome relate to excess activation and signaling by the growth factor TGF-beta (Dietz_2005)." This variant determines the substitution of cysteine with tyrosine. The sulfhydryl group of cysteine is unique in its ability to participate in disulfide covalent cross-linkage. In fact, two thirds of fibrillin cysteine residues exist in the half-cystinyl form, suggesting their participation in intramolecular disulfide linkage. Therefore, alteration of cysteine in this domain could disrupt disulfide binding, effecting secondary or tertiary structure or possibly impairing fibrillin interactions. Additionally, this variant was reported in a patient with Marfan syndrome. No clinical laboratories cite the variant of interest. Therefore, taking all available lines of evidence, the variant of interest is classified as VUS-possibly pathogenic until additional information becomes available.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826164 SCV000967701 likely pathogenic Marfan syndrome 2018-02-08 criteria provided, single submitter clinical testing The p.Cys2339Tyr variant in FBN1 has been reported in 1 individual with clinical features of Marfan syndrome (Katzke 2002) and was absent from large population studies. Computational prediction tools and conservation analysis suggest that t he p.Cys2339Tyr variant may impact the protein. Two other variants at this amino acid position (p.Cys2239Gly, p.Cys2239arg) have also been reported in individua ls with Marfan syndrome (Rybczynski 2008, Ogawa 2011), suggesting that changes a t this position may not be tolerated. In addition, the p.Cys2339Tyr variant affe cts a cysteine residue; cysteine substitutions are a common finding in individua ls with Marfan syndrome (Schrijver 1999). In summary, although additional studie s are required to fully establish its clinical significance, the p.Cys2339Tyr va riant is likely pathogenic. ACMG/AMP Criteria applied (Richards 2015): PM1; PM2; PP3; PS4_supporting.

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