Submissions for variant NM_000138.5(FBN1):c.5726T>C (p.Ile1909Thr)

dbSNP: rs794728333

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181696	SCV000233999	uncertain significance	not provided	2015-10-13	criteria provided, single submitter	clinical testing	The I1909T variant in the FBN1 gene has been reported previously in a seven year-old male meeting diagnostic criteria for Marfan syndrome (Loeys et al., 2001). Additionally, this variant was listed in a study validating the detection of mutations in individuals with Marfan and Loeys-Dietz syndrome by massive parallel sequencing (Baetens et al., 2011). This variant has been observed in one other individual referred for genetic testing of Marfan syndrome/TAAD at GeneDx. The I1909T variant 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. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. Missense variants in nearby residues have been reported in association with Marfan syndrome (Stenson et al, 2014). However, while the I1909T variant is located in a calcium-binding EGF-like domain of the fibrillin-1 protein, it does not affect a Cysteine residue within this domain. Cysteine substitutions in calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003). Furthermore, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.In summary, additional evidence is needed to determine whether this variant is pathogenic or a rare benign variant
Ambry Genetics	RCV000253306	SCV000318851	likely pathogenic	Cardiovascular phenotype	2020-01-09	criteria provided, single submitter	clinical testing	The p.I1909T variant (also known as c.5726T>C), located in coding exon 46 of the FBN1 gene, results from a T to C substitution at nucleotide position 5726. The isoleucine at codon 1909 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in several individuals with Marfan syndrome (Loeys B et al. Arch. Intern. Med., 2001 Nov;161:2447-54; Baetens M et al. Hum. Mutat., 2011 Sep;32:1053-62; Ambry internal data). This amino acid position is not well conserved in available vertebrate species; however, all available vertebrate species have either isoleucine or the highly similar valine as the reference amino acid. 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.
Invitae	RCV000803899	SCV000943787	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1909 of the FBN1 protein (p.Ile1909Thr). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ile1909 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 19293843), 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) 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. ClinVar contains an entry for this variant (Variation ID: 200189). This missense change has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 11700157, 21542060, 33230159; Invitae). In at least one individual the variant was observed to be de novo.
Centre of Medical Genetics, University of Antwerp	RCV000663811	SCV002025357	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS1, PP4
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000663811	SCV004013970	pathogenic	Marfan syndrome	2023-06-13	criteria provided, single submitter	clinical testing	PS4, PM1, PM2, PP3, PP5
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000663811	SCV004034103	pathogenic	Marfan syndrome	2023-07-01	criteria provided, single submitter	research
Center for Medical Genetics Ghent, University of Ghent	RCV000663811	SCV000787163	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing