Submissions for variant NM_000138.5(FBN1):c.2433C>A (p.Cys811Ter)

dbSNP: rs193921256

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002310635	SCV000319270	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2020-07-07	criteria provided, single submitter	clinical testing	The p.C811* pathogenic mutation (also known as c.2433C>A), located in coding exon 20 of the FBN1 gene, results from a C to A substitution at nucleotide position 2433. This changes the amino acid from a cysteine to a stop codon within coding exon 20. In a study of Taiwanese patients with Marfan syndrome, this mutation was detected in an individual fulfilling Ghent criteria with cardiovascular, ocular, and dural manifestations; this variant was also reported in one individual from a Polish Marfan syndrome cohort (Hung CC et al. Ann. Hum. Genet., 2009 Nov;73:559-67; Wypasek E et al. Pol. Arch. Med. Wewn., 2013;123:646-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000493454	SCV000583320	pathogenic	not provided	2017-05-18	criteria provided, single submitter	clinical testing	The C811X pathogenic variant in the FBN1 gene has been previously reported in association with Marfan syndrome (Hung et al., 2009; Wypasek et al., 2013). Hung et al. (2009) identified C811X in a Taiwanese patient or family fulfilling Ghent criteria for Marfan syndrome, although specific clinical information was not provided. Subsequently, Wypasek et al. (2013) reported C811X in a Polish female proband with Marfan syndrome. While the proband had several maternal relatives with clinical histories suspicious for Marfan syndrome, genetic testing of informative relatives was not performed at the time of publication (Wypasek et al., 2013). The C811X variant is classified in ClinVar as pathogenic or likely pathogenic by two other clinical laboratories (SCV000052362.1, SCV000319270.1; Landrum et al., 2016). C811X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Multiple other nonsense variants in the FBN1 gene have been reported in Human Gene Mutation Database in association with FBN1-related disorders, including Marfan syndrome (Stenson et al., 2014). Furthermore, the C811X 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	RCV000588833	SCV000695487	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2016-02-10	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000493454	SCV005197889	pathogenic	not provided	2023-05-04	criteria provided, single submitter	clinical testing
Center for Medical Genetics Ghent, University of Ghent	RCV000663539	SCV000786850	pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing