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MFS is primarily caused by pathogenic alterations in <jats:italic>FBN1<\/jats:italic>, which encodes the fibrillin\u20101 protein. Fibrillin\u20101 comprises multiple domains rich in cysteine residues, with disulfide bonds formed between these residues. It has long been recognized that variants that alter or introduce cysteine residues damage protein function, leading to the development of MFS. In this study, we report a cysteine\u2010introducing variant: <jats:italic>FBN1<\/jats:italic> variant, c.6724C&gt;T (p.[Arg2242Cys]). We have observed this variant in several individuals without MFS, challenging our previous understanding of the underlying mechanism of MFS. This finding emphasizes the importance of revisiting and reevaluating our current knowledge in light of new and unexpected observations. Moreover, our study highlights the significance of incorporating local and national data on allele frequencies, as well as employing multidisciplinary phenotyping approaches, in the classification of genetic variants. By considering a wide range of information, we can enhance the accuracy and reliability of variant classification, ultimately improving the diagnosis and management of individuals with genetic disorders like MFS.<\/jats:p>","DOI":"10.1002\/ajmg.a.63795","type":"journal-article","created":{"date-parts":[[2024,6,22]],"date-time":"2024-06-22T02:23:01Z","timestamp":1719022981000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Reclassification of an <i>FBN1<\/i> variant emphasizes the importance of segregation analysis, information sharing, and multidisciplinary teamwork in understanding genetic variants in health and disease"],"prefix":"10.1002","volume":"194","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0223-1673","authenticated-orcid":false,"given":"Dorte L.","family":"Lildballe","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine Aarhus University Hospital  Aarhus Denmark"},{"name":"Department of Clinical Medicine Aarhus University  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Markholt","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Aarhus University Hospital  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina Daugaard","family":"Lyngholm","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Aarhus University Hospital  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Odense University Hospital  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Fagerberg","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Odense University Hospital  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorte Guldbrand","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Department of Cardiology Aarhus University Hospital  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julius Hannibal","family":"Svensmark","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Copenhagen University Hospital Rigshospitalet  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgitte Rode","family":"Diness","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Copenhagen University Hospital Rigshospitalet  Copenhagen Denmark"},{"name":"Department of Clinical Medicine Copenhagen University  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3424-0590","authenticated-orcid":false,"given":"Pernille A.","family":"Gregersen","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine Aarhus University  Aarhus Denmark"},{"name":"Department of Clinical Genetics Aarhus University Hospital  Aarhus Denmark"},{"name":"Centre for Rare Diseases, Department of Pediatrics and Adolescent Medicine Aarhus University Hospital  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,6,21]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.21037\/cdt-20-692"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-021-01132-x"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-019-0440-3"},{"key":"e_1_2_11_5_1","unstructured":"ClinGen. 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