ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.5504G>A (p.Cys1835Tyr) (rs111929350)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035227 SCV000058872 likely pathogenic Marfan syndrome 2012-05-22 criteria provided, single submitter clinical testing The Cys1835Tyr variant has been reported in 2 individuals with clinical features of Marfan syndrome (Halliday 1999, Loeys 2001). Functional studies using patien t-derived fibroblasts have shown that the Cys1835Tyr variant impacts the extrace llular secretion of fibrillin-1 (Halliday 1999). However, this cellular system m ay not accurately represent biological function. This residue is highly conserve d across species and computational analyses (biochemical amino acid properties, PolyPhen2, and SIFT) suggest that this variant may impact the protein, though th is information is not predictive enough to determine pathogenicity. The Cys1835T yr variant has been identified in 0.01% (1/1128) of chromosomes from a broad, th ough clinically and racially unspecified population (dbSNP rs111929350). This fr equency is not high enough to rule out a pathogenic role. Lastly, this variant a ffects a cysteine residue. Cysteine substitutions are a common finding in indivi duals with Marfan syndrome (Schrijver 1999). In summary, this variant is likely to be pathogenic, though further segregation studies and functional analyses are required to fully establish the pathogenicity of this variant.
GeneDx RCV000181545 SCV000233848 pathogenic not provided 2014-08-12 criteria provided, single submitter clinical testing p.Cys1835Tyr (TGT>TAT): c.5504 G>A in exon 45 of the FBN1 gene (NM_000138.4)The C1835Y mutation in the FBN1 gene has been reported in multiple unrelated individuals with classic Marfan syndrome (Loeys B et al., 2001; Matyas G et al., 2002; Conmeglio P et al., 2007). C1835Y results in a non-conservative amino acid substitution resulting in a loss of a Cysteine residue, which may impact disulfide bonding, at a position that is conserved across species. Other mutations in this residue (C1835F) and in nearby residues (C1833S, C1833R, P1837S) have been reported in association with Marfan syndrome, further supporting the functional importance of this residue and this region of the protein. Furthermore, the C1835Y mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, C1835Y in the FBN1 gene is interpreted as a disease-causing mutation. The variant is found in TAAD panel(s).

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