ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1817C>A (p.Ser606Ter) (rs794728176)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181442 SCV000233744 pathogenic not provided 2018-01-22 criteria provided, single submitter clinical testing Although the S606X variant in the FBN1 gene has not been reported as a pathogenic or benign to our knowledge, it has been observed in other individuals referred for connective tissue disorder genetic testing at GeneDx. The S606X variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Furthermore, multiple other nonsense variants in the FBN1 gene have been reported in Human Gene Mutation Database in association with Marfan syndrome (Stenson et al., 2014). Finally, the S606X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001201314 SCV001372456 likely pathogenic Familial aortopathy 2020-06-26 criteria provided, single submitter clinical testing Variant summary: FBN1 c.1817C>A (p.Ser606X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251324 control chromosomes. To our knowledge, no occurrence of c.1817C>A in individuals affected with Marfan syndrome/Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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