Submissions for variant NM_000138.5(FBN1):c.1545_1546inv (p.Cys515_Arg516delinsTrpGly)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003120250	SCV003800287	pathogenic	not provided	2022-04-21	criteria provided, single submitter	clinical testing	The FBN1 c.1545_1546delinsGG; p.Cys515_Arg516delinsTrpGly variant is reported in the literature to segregate with a clinical diagnosis of Marfan syndrome in a large family (Villamizar 2010). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant involves a cysteine residue in one of the calcium binding EGF-like domains of fibrillin-1 (Wu 1995). Each EGF-like domain contains six highly-conserved cysteines and the disulfide bridges formed between these residues are essential for protein folding; loss of one of these cysteines may interfere with proper disulfide bridge formation, disrupting protein structure. Accordingly, the revised Ghent nosology for Marfan syndrome lists loss of cysteine residues as one of the criteria for classification of a variant as pathogenic (Loeys 2010). Based on available information, this variant is considered to be pathogenic. References: Loeys BL et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 Jul;47(7):476-85. PMID: 20591885. Villamizar C et al. Paucity of skeletal manifestations in Hispanic families with FBN1 mutations. Eur J Med Genet. 2010 Mar-Apr;53(2):80-4. PMID: 19941982. Wu YS et al. Fibrillin domain folding and calcium binding: significance to Marfan syndrome. Chem Biol. 1995 Feb;2(2):91-7. PMID: 9383409.
GeneDx	RCV003120250	SCV004021546	likely pathogenic	not provided	2023-07-18	criteria provided, single submitter	clinical testing	Affects a 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); Identified in a patient with ascending aortic dissection and ectopia lentis and was identified in 7 other family members with ocular and/or cardiovascular features of Marfan syndrome; however, skeletal features were not present in any members of this family (Villamizer et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10486319, 12938084, 19941982)