Submissions for variant NM_000138.5(FBN1):c.1169C>T (p.Ser390Phe)

gnomAD frequency: 0.00001  dbSNP: rs746385384

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000687688	SCV000815273	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-06-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001204	SCV001158364	uncertain significance	not specified	2019-04-25	criteria provided, single submitter	clinical testing	The FBN1 c.1169C>T; p.Ser390Phe variant (rs746385384) is reported in the medical literature in an individual with craniosynostosis, but the variant was not determined to be causative (Clarke 2018). The variant is listed in the ClinVar database (Variation ID: 549007) and in the general population in 6 out of 244982 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at this position is weakly conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is tolerated. Considering available information, the clinical significance of this variant is uncertain at this time.
Color Diagnostics, LLC DBA Color Health	RCV001182275	SCV001347671	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 390 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 been identified in 6/250224 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.
All of Us Research Program, National Institutes of Health	RCV000663445	SCV004823075	uncertain significance	Marfan syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 390 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/250224 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.
Center for Medical Genetics Ghent, University of Ghent	RCV000663445	SCV000786737	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354497	SCV001549129	uncertain significance	not provided		no assertion criteria provided	clinical testing	The FBN1 p.Ser390Phe variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs746385384) and ClinVar (classified as a VUS by Invitae and Center for Medical Genetics Ghent, University of Ghent for Marfan Syndrome and Thoracic aortic aneurysm and aortic dissection). The variant was identified in control databases in 6 of 250224 chromosomes at a frequency of 0.000024 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (non-Finnish) population in 6 of 112904 chromosomes (freq: 0.000053), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The p.Ser390 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.