Submissions for variant NM_000138.5(FBN1):c.5743C>T (p.Arg1915Cys)

dbSNP: rs1555395826

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000663814	SCV004704621	pathogenic	Marfan syndrome	2024-02-22	reviewed by expert panel	curation	The NM_00138 c.5743C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 1915 (p.Arg1915Cys) within a calcium binding EGF-like domain of the protein (PM1). This variant was found in a proband with classical Marfan syndrome (MFS) (Internal lab data, PP4). This variant has been reported 6 times in ClinVar: once as pathogenic, 4 times as likely pathogenic, and once as uncertain significance (Variation ID: 495629). This variant has also been identified in at least 7 individuals with clinical diagnosis of MFS as well as in individuals with clinical features of MFS (PMID 27234404, 35916808, 33174221, 27906200, internal data; PS4). In two families with MFS, the variant was found to segregate with disease in three affected relatives (Internal lab data, PP1). Different missense variants at this position, c.5744G>A p.(Arg1915His) and c.5743C>A p.(Arg1915Ser), have previously been reported in individuals with MFS and/or MFS-related features (PMID 11700157, 31830381), however these variants have not yet been reviewed by 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 are inconclusive with regards to a possible impact on this variant's protein function and structure (REVEL: 0.62). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PM1, PP1, PM2_Sup, PP2, PP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589788	SCV000695568	likely pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2016-03-29	criteria provided, single submitter	clinical testing	Variant summary: This FBN1 c.5743C>T variant affects a highly conserved nucleotide, resulting in amino acid change from Arg to Cys at codon 1915 in the calcium binding EGF-like #28 domain. Cysteine substitution in such domains is known to disrupt the secondary structure of FBN1 protein and possibly impairing fibrillin interactions. 3/4 in-silico tools predict this variant to be damaging, however no functional studies have been published on this missense mutation. This variant was not found in approximately 121094 control chromosomes from the broad and large populations of ExAC. To our knowledge, the variant has not been reported in peer reviewed publications, but has been cited in one MFS patient in the UMD database and 1 familial case referred for genetic testing at our facility. Another missense variant in the same codon, p.R1915S, has been reported in a MFS patient (PMID: 11700157). In addition, there are multiple missense variants (such as p.N1907H, p.N1907K, p.N1907S, p.T1908I, p.I1909S, p.I1909T, p.G1910V, p.F1912C, p.R1915S, p.C1916S, p.C1916Y, etc; source HGMD) in this region that are found in MFS patients indicating that the region or this codon is functionally important. Taken together, mainly based on the nature of this variant in the EGF-like domain, FBN1 c.5743C>T has currently been classified as Likely Pathogenic.
Invitae	RCV001240585	SCV001413547	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1915 of the FBN1 protein (p.Arg1915Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Marfan syndrome (PMID: 27234404, 27906200, 33174221; Invitae). ClinVar contains an entry for this variant (Variation ID: 495629). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN1 protein function. This variant disrupts the p.Arg1915 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 11700157, 27906200, 31830381), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
DASA	RCV000663814	SCV002526389	likely pathogenic	Marfan syndrome	2022-06-10	criteria provided, single submitter	clinical testing	The c.5743C>T;p.(Arg1915Cys) missense change has been observed in affected individual(s)(PMID: 27906200) - PS4_supporting. The variant is located in a mutational hot spot and/or critical and well-established functional domain (EGF-like domain) - PM1. This variant is not present in population databases:rs1555395826, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported and classified as Pathogenic by ACMG criteria (c.5743C>A;p.(Arg1915Ser) - PMID: 27906200) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Likely Pathogenic
MGZ Medical Genetics Center	RCV000663814	SCV002580949	likely pathogenic	Marfan syndrome	2022-06-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004024673	SCV005032634	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-09-20	criteria provided, single submitter	clinical testing	The p.R1915C variant (also known as c.5743C>T), located in coding exon 46 of the FBN1 gene, results from a C to T substitution at nucleotide position 5743. The arginine at codon 1915 is replaced by cysteine, an amino acid with highly dissimilar properties. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). This variant has been detected in individuals reported to have Marfan syndrome (MFS) or features consistent with MFS (Yang H et al. Clin Chim Acta, 2016 Aug;459:30-35; Hernándiz A et al. Clin Genet, 2021 Feb;99:269-280; Andreescu N et al. Eur Rev Med Pharmacol Sci, 2022 Jul;26:5107-5114; external communication). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Center for Medical Genetics Ghent, University of Ghent	RCV000663814	SCV000787166	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000663814	SCV001192850	likely pathogenic	Marfan syndrome	2017-08-09	no assertion criteria provided	clinical testing