Submissions for variant NM_000138.5(FBN1):c.5347A>T (p.Ile1783Phe)

gnomAD frequency: 0.00001  dbSNP: rs1232797551

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541663	SCV000627935	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-05-13	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1783 of the FBN1 protein (p.Ile1783Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of FBN1-related conditions (PMID: 31829210). ClinVar contains an entry for this variant (Variation ID: 457229). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001179632	SCV001344341	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with phenylalanine at codon 1783 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with FBN1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV002510913	SCV002820773	uncertain significance	not provided	2022-07-15	criteria provided, single submitter	clinical testing	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; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; 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); Identified in an individual with a Progeroid phenotype in published literature (Grelet M et al., 2019), additional details were not provided; This variant is associated with the following publications: (PMID: 12938084, 31829210)
All of Us Research Program, National Institutes of Health	RCV004003790	SCV004814662	uncertain significance	Marfan syndrome	2023-02-24	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the calcium-binding EGF-like motif 29 of the FBN1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.