ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2243G>A (p.Cys748Tyr) (rs1064794282)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486760 SCV000568641 likely pathogenic not provided 2016-05-06 criteria provided, single submitter clinical testing The C748Y likely pathogenic variant in the FBN1 gene has been reported previously in association with Marfan syndrome and was observed to segregate with disease in at least one relative (Katzke et al., 2002; Halliday et al.,2002; Hung et al., 2009). The C748Y variant was also identified in a Jordanian patient with tall stature and suspected Marfan syndrome, though additional clinical data were unavailable (Jaradat et al., 2015). In addition, C748Y was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Moreover, the C748Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and this substitution occurs at a position that is conserved across species. Finally, the C748Y 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 Marfan syndrome (Collod-Beroud et al., 2003). In silico analysis predicts this variant is probably damaging to the protein structure/function.Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588016 SCV000695481 pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2021-02-22 criteria provided, single submitter clinical testing Variant summary: FBN1 c.2243G>A (p.Cys748Tyr) results in a non-conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251436 control chromosomes. c.2243G>A has been reported in the literature in multiple individuals affected with Marfan Syndrome (e.g. Katzke_2002, Hung_2009, Xu_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, this variant disrupts one of the cysteine residues in the EGF-like domain, which are known to play an important role in protein structure and interactions with other molecules, suggesting that the variant could affect protein function (e.g. Dietz_1992). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000696385 SCV000824945 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2018-09-04 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 748 of the FBN1 protein (p.Cys748Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Marfan syndrome (PMID: 12203992, 19839986, 12161601, 26770496). ClinVar contains an entry for this variant (Variation ID: 420086). This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). The observation of one or more missense substitutions at this codon (p.Cys748Tyr and p.Cys748Arg) in affected individuals suggests that this may be a clinically significant residue (PMID: 19839986, 29357934). For these reasons, this variant has been classified as Pathogenic.

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