Submissions for variant NM_000138.5(FBN1):c.8378A>G (p.Tyr2793Cys)

dbSNP: rs397515863

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000035289	SCV005387633	likely pathogenic	Marfan syndrome	2024-08-22	reviewed by expert panel	curation	The NM_00138 c.8378A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 2793 (p.Tyr2793Cys), located within the C-terminal region of the protein. This variant was found in a proband with thoracic aortic dissection and a systemic score >7, which is a highly specific phenotype for Marfan syndrome (MFS) (Internal lab data, PP4). This variant has been reported three times in ClinVar: once as likely pathogenic, 2 times as uncertain significance (Variation ID: 42443). This variant has also been identified in at least 1 individual with a clinical diagnosis of MFS, as well as in individuals with clinical features of MFS (PMID 17663468, 34916231, 37558401, Invitae ClinVar, PS4_Moderate). A different missense variant at this position, c.8377T>C p.Tyr2793His, has previously been reported in individuals with MFS and/or MFS-related features (PMID 21542060, ClinVar), however the p.Tyr2793His variant has not yet been reviewed the FBN1 Variant Curation Expert Panel. This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.967, PP3). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; https://gnomad.broadinstitute.org/ v4.0.0). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4_Moderate, PM2_Sup, PP2, PP3, PP4.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844629	SCV000058937	uncertain significance	not specified	2019-02-14	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631997	SCV000753100	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-09-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr2793 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 21542060), which suggests that this may be a clinically significant amino acid residue. 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: 42443). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 17253931; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2793 of the FBN1 protein (p.Tyr2793Cys).
Center for Medical Genetics Ghent, University of Ghent	RCV000035289	SCV000787412	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing
Department of Laboratory Medicine and Genetics, Samsung Medical Center	RCV000035289	SCV005684927	pathogenic	Marfan syndrome	2025-01-02	no assertion criteria provided	clinical testing	The NM_000138.5:c.8378A>G is considered to be rare in the general population database (gnomAD v2.1.1). This variant is predicted to be deleterious by in-silico analysis (REVEL). This variant is located in functional domains. This variant was found in a patient with Marfan syndrome meeting Ghent criteria (PMID: 17253931). According to the ClinGen guidance for PP1/BS4 and PP4 criteria (PMID: 38103548), PP4 with weighted strength was applied. In summary, this variant was classified as a pathogenic variant for Marfan syndrome (PM1, PP2, PP3, PP4 with weighted strength, PM2_P).