Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000181442 | SCV000233744 | pathogenic | not provided | 2021-04-01 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease |
| Women's Health and Genetics/Laboratory Corporation of America, |
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. |
| Laboratory for Molecular Medicine, |
RCV004017456 | SCV004847707 | likely pathogenic | Marfan syndrome | 2019-04-16 | criteria provided, single submitter | clinical testing | The p.Ser606X variant in FBN1 has not been previously reported in individuals with Marfan syndrome and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 199979). This nonsense variant leads to a premature termination codon at position 606, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the FBN1 gene is an established disease mechanism in Marfan syndrome. In summary, although additional studies are required to fully establish its clinical significance, the p.Ser606X variant meets criteria to be classified as likely pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PVS1, PM2. |