Submissions for variant NM_000138.5(FBN1):c.4364T>G (p.Ile1455Ser)

dbSNP: rs397515807

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003441728	SCV000058840	uncertain significance	not provided	2023-04-28	criteria provided, single submitter	clinical testing	The p.Ile1455Ser (c.4364T>G) variant in FBN1 has been reported in 1 individual with aortic dilatation (Lerner-Ellis 2014 PMID: 24793577) and was identified in three relatives with some clinical Marfan features, which do not meet Ghent criteria, and one asymptomatic relative. Another relative with some clinical Marfan features did NOT carry this variant (LMM Internal Data). It was absent from gnomAD. This variant has also been reported in ClinVar (Variation ID 42359). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3.
Color Diagnostics, LLC DBA Color Health	RCV001525489	SCV001735622	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-06-01	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with serine at codon 1455 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). Splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having Marfan syndrome (PMID: 24793577). This variant has been identified in 1/251286 chromosomes 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852710	SCV002185634	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1455 of the FBN1 protein (p.Ile1455Ser). This variant is present in population databases (rs397515807, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of FBN1-related conditions (PMID: 24793577; internal data). ClinVar contains an entry for this variant (Variation ID: 42359). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
GeneDx	RCV003441728	SCV004169109	uncertain significance	not provided	2023-10-20	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; In silico analysis supports a deleterious effect on splicing; 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); Reported in a patient with suspected Marfan syndrome in published literature (Lerner-Ellis et al., 2014); This variant is associated with the following publications: (PMID: 24793577)
All of Us Research Program, National Institutes of Health	RCV000035198	SCV004814734	uncertain significance	Marfan syndrome	2023-06-27	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with serine at codon 1455 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). Splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having Marfan syndrome (PMID: 24793577). This variant has been identified in 1/251286 chromosomes 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.