Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV003476882 | SCV004218523 | likely pathogenic | Marfan syndrome | 2023-12-29 | reviewed by expert panel | curation | NM_000138.5 c.4407_4409dup is a duplication of 3 nucleotides in FBN1 predicted to cause the duplication of the cysteine residue at amino acid position 1470 (p.Cys1470dup). This variant has been identified in at least two individuals with suspicion for Marfan syndrome including a proband with several systemic features and a proband with tall stature and thoracic aortic aneurysm and dissection (TAAD) (PS4_supporting; GeneDx internal data). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/ v2.1.1 & v3.1.2). This in-frame insertion introduces a novel cysteine residue which may impede the normal formation of essential disulfide bridges (PM1, PM4). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM4, PM2_supporting, PS4_supporting. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000585977 | SCV000695540 | uncertain significance | not provided | 2016-01-12 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000585977 | SCV002549196 | likely pathogenic | not provided | 2022-07-05 | criteria provided, single submitter | clinical testing | In-frame insertion of 1 amino acid in a non-repeat region; Introduces a new 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 FBN1-related disorders (Collod-Beroud et al., 2003); Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge |