ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.7916A>G (p.Tyr2639Cys) (rs794728280)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617441 SCV000738915 pathogenic Cardiovascular phenotype 2017-07-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Strong segregation with disease (lod >3 = >10 meioses),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770653 SCV000902111 likely pathogenic Thoracic aortic aneurysm and aortic dissection 2016-12-06 criteria provided, single submitter clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000663995 SCV000787379 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
GeneDx RCV000181620 SCV000233923 pathogenic not provided 2013-01-24 criteria provided, single submitter clinical testing p.Tyr2639Cys (Y2639C): c.7916 A>G (TAT>TGT) in the FBN1 gene (NM_000138.4) The Y2639C missense mutation in the FBN1 gene has been reported previously in association with Marfan syndrome (Aalberts et al., 2010). The authors identified the Y2639C mutation in 11 affected members of a large Dutch multi-generational family who fulfilled the Ghent diagnostic criteria for Marfan syndrome. Another seemingly unrelated individual with Marfan syndrome was also found to be heterozgous for this mutation (Aalberts et al., 2010). The mutation results in a non-conservative replacement of a Tyrosine residue with a Cysteine residue at a highly conserved position within the calcium-binding epidermal growth factor (EGF)-like domain 42. As Cysteine residues are crucial in stabilizing the EGF-like domains in fibrillin, introducing a Cysteine at amino acid position 2639 is likely to impact formation of disulfide bonds and affect protein stability (Aalberts et al., 2010). The variant is found in TAAD panel(s).
Integrated Genetics/Laboratory Corporation of America RCV000586564 SCV000695612 pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2017-08-25 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.7916A>G (p.Tyr2639Cys) variant involves the alteration of a conserved amino acid residue located in the EGF-like calcium-binding domain (IPR001881) (InterPro). Cysteine residues are critical in stabilization of EGF-like domains in fibrillin, thus introducing a new cysteine residue is predicted to disturb disulphide bonding and affect protein stability (Aalberts 2010). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index), however these have not been investigated by functional studies. This variant has been reported in multiple patients affected by the Marfan syndrome spectrum, with a strong family history of which many fulfilled the Ghent diagnostic criteria (Aalberts 2010, Poninska 2016). This variant is absent in 121400 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

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