Submissions for variant NM_000138.5(FBN1):c.3146G>A (p.Gly1049Asp)

dbSNP: rs1555398670

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317292	SCV000695503	likely pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2023-06-21	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.3146G>A (p.Gly1049Asp) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) 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 251486 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3146G>A has been reported in the literature as a likely pathogenic variant in an individual affected with Marfan Syndrome and as a VUS in an individual affected with isolated thoracic aortic aneurysm (example, Meester_2021, Li_2021). It has also been observed to segregate with features of Marfan disease among individual(s) from a family referred for Marfan testing at our laboratory. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33824467, 35058154). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=1) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000820499	SCV000961215	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-09-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly1049 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 495585). This missense change has been observed in individual(s) with isolated thoracic aortic aneurysm and/or Marfan syndrome (PMID: 33824467; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1049 of the FBN1 protein (p.Gly1049Asp).
Department of Vascular Biology, Beijing Anzhen Hospital	RCV001374765	SCV001439546	uncertain significance	Isolated thoracic aortic aneurysm	2018-09-01	criteria provided, single submitter	research
Centre of Medical Genetics, University of Antwerp	RCV002246000	SCV002025566	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS6, PP4