Submissions for variant NM_000138.5(FBN1):c.1100C>T (p.Ser367Phe)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002647286	SCV003513994	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-10-02	criteria provided, single submitter	clinical testing	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. 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. This variant has not been reported in the literature in individuals affected with FBN1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 367 of the FBN1 protein (p.Ser367Phe).
Ambry Genetics	RCV003162020	SCV003863077	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-11-10	criteria provided, single submitter	clinical testing	The p.S367F variant (also known as c.1100C>T), located in coding exon 9 of the FBN1 gene, results from a C to T substitution at nucleotide position 1100. The serine at codon 367 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant has been detected in a proband from a sudden unexpected death in epilepsy cohort who was not indicated as having cardiovascular findings and carried additional genetic variants (Coll M et al. Int J Legal Med, 2016 Mar;130:331-9). This amino acid position is 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.
All of Us Research Program, National Institutes of Health	RCV004009490	SCV004838858	uncertain significance	Marfan syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 367 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 been reported in an individual who was affected with generalized epilepsy and experienced sudden unexpected death (PMID: 26423924). 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.