ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.6032G>A (p.Cys2011Tyr) (rs886038967)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000242615 SCV000319401 uncertain significance Cardiovascular phenotype 2015-03-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000413845 SCV000490525 likely pathogenic not provided 2016-11-02 criteria provided, single submitter clinical testing The C2011Y variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, this variant has been classified in ClinVar as a variant of uncertain significance by another clinical laboratory (ClinVar SCV000319401.1; Landrum et al., 2016). The C2011Y variant 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. The C2011Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, the C2011Y variant affects a Cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003). However, to our knowledge no studies have been performed to determine the functional effect of the C2011Y variant.Therefore, this variant is likely pathogenic.

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