Submissions for variant NM_000138.5(FBN1):c.3409C>T (p.Arg1137Cys)

gnomAD frequency: 0.00001  dbSNP: rs1439487763

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV003476885	SCV004218530	uncertain significance	Marfan syndrome	2023-12-29	reviewed by expert panel	curation	The NM_00138 c.3409C>T is a missense variant in FBN1 predicted to cause a substitution of a an arginine by cysteine at amino acid 1137 (p. Arg1137Cys) within a calcium binding EGF-like domain of the protein. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure and this variant may impact disulfide bonding (PM1). This variant has been reported four times in ClinVar: twice as likely pathogenic and twice as uncertain significance (Variation ID: 928903). To our knowledge, this variant has not previously been reported in individuals affected with Marfan syndrome in the literature. This variant is present in 3/74922 (0.004%) of alleles tested from the African/African American population gnomAD (https://gnomad.broadinstitute.org/ v4.0.0). A different missense variant affecting the same residue, p.Arg1137Pro, has been previously reported in individuals with Marfan syndrome and was observed to de novo (PMID 1852208, PM5). Computational prediction tools and conservation analysis are inconclusive data with regards to a possible impact on this variant protein function and structure (REVEL: 0.736). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). Due to the conflicting evidence, this variant is classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM5, PP2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193507	SCV001362392	uncertain significance	not specified	2019-06-17	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.3409C>T (p.Arg1137Cys) results in a non-conservative amino acid change located in the EGF-like calcium-binding domain (IPR001881) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. "The sulfhydryl group of cysteine is unique in its ability to participate in disulfide covalent cross-linkage. In fact, two-thirds of fibrillin cysteine residues exist in the half-cystinyl form, suggesting their participation in intramolecular disulfide linkage. The cysteine residues in the EGF-like motif may also be necessary for intermolecular interactions with other fibrillin molecules or with other proteins (Dietz_1992)." Therefore, alteration of cysteine in this domain could disrupt disulfide binding, effecting secondary or tertiary structure or possibly impairing fibrillin interactions. The variant allele was found at a frequency of 4e-06 in 251482 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3409C>T in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx	RCV001847186	SCV002104486	likely pathogenic	not provided	2022-11-04	criteria provided, single submitter	clinical testing	Introduces a new 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); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 12938084)
Invitae	RCV001876252	SCV002280093	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-11-08	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 1137 of the FBN1 protein (p.Arg1137Cys). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 928903). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg1137 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1852208). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002451403	SCV002614359	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-06-06	criteria provided, single submitter	clinical testing	The p.R1137C variant (also known as c.3409C>T), located in coding exon 27 of the FBN1 gene, results from a C to T substitution at nucleotide position 3409. The arginine at codon 1137 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 amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004538429	SCV004115499	uncertain significance	FBN1-related disorder	2023-07-01	criteria provided, single submitter	clinical testing	The FBN1 c.3409C>T variant is predicted to result in the amino acid substitution p.Arg1137Cys. To our knowledge, this variant has not been reported in the literature. This variant is located in the epidermal growth factor-like domain of the FBN1 protein. Missense variants in FBN1 that substitute or create a cysteine residue are documented to cause Marfan syndrome (Dietz and Dietz. 1993. PubMed ID: 20301510; Comeglio et al. 2007. PubMed ID: 17657824; Stheneur et al. 2009. PubMed ID: 19293843). This variant is reported in 0.0099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-48779563-G-A) and has conflicting interpretations of pathogenicity in ClinVar ranging from likely pathogenic to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/928903). A different nucleotide substitution affecting the same amino acid (p.Arg1137Pro) has been reported de novo in two individuals with Marfan syndrome (described as R239P, Dietz et al. 1991. PubMed ID: 1852208). Taken together, although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001847186	SCV004564309	uncertain significance	not provided	2023-01-11	criteria provided, single submitter	clinical testing	The FBN1 c.3409C>T; p.Arg1137Cys variant (rs1439487763), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 928903). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, another variant at this codon (c.3410G>C, p.Arg1137Pro) has been reported in individuals with Marfan syndrome and is considered likely pathogenic (Dietz 1991). The arginine at codon 1137 is highly conserved, it occurs in a conserved residue of an EGF domain consensus sequence, and computational analyses predict that this variant is deleterious (REVEL: 0.736). However, given the lack of clinical and functional data, the significance of the p.Arg1137Cys variant is uncertain at this time. References: Dietz HC et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 1991 Jul 25;352(6333):337-9. PMID: 1852208.
All of Us Research Program, National Institutes of Health	RCV003476885	SCV004828839	uncertain significance	Marfan syndrome	2023-06-27	criteria provided, single submitter	clinical testing