Submissions for variant NM_000138.5(FBN1):c.4467T>A (p.Asn1489Lys)

dbSNP: rs193922205

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855643	SCV000695543	likely pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2023-05-22	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.4467T>A (p.Asn1489Lys) results in a non-conservative amino acid change located in the EGF-like calcium-binding and EGF-like domains of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251118 control chromosomes. c.4467T>A has been reported in the literature in individuals affected with Marfan Syndrome (examples- Baetens_2011, Regalado_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21542060, 20082464, 24793577, 25907466, 26621581, 30371227, 35058154). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 . Multiple laboratories reported the variant with conflicting assessments: Pathogenic (n=1), Likely Pathogenic (n=4) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV001046640	SCV001210551	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-04-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 36076). This missense change has been observed in individuals with thoracic aortic aneurysm and dissection (PMID: 20082464, 21542060, 26621581; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1489 of the FBN1 protein (p.Asn1489Lys).
Centre of Medical Genetics, University of Antwerp	RCV000029738	SCV002025320	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS1, PP4
GeneDx	RCV001843461	SCV002102630	likely pathogenic	not provided	2023-09-19	criteria provided, single submitter	clinical testing	Reported to segregate with aortic aneurysm and/or aortic dissection in three members from a single family without a clinical diagnosis of Marfan syndrome (Regalado et al., 2015); 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; This variant is associated with the following publications: (PMID: 24793577, 30371227, 25907466, 20082464, 26621581, 21542060, 20591885, 35058154)
Ambry Genetics	RCV002326690	SCV002638901	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2016-10-28	criteria provided, single submitter	clinical testing	The p.N1489K variant (also known as c.4467T>A), located in coding exon 36 of the FBN1 gene, results from a T to A substitution at nucleotide position 4467. The asparagine at codon 1489 is replaced by lysine, an amino acid with some similar properties. This variant was described in a patient reported to have a diagnosis of Marfan syndrome (MFS) (Baetens M et al. Hum Mutat. 2011;32(9):1053-62). It was also reported in a patient with primary descending thoracic aortic dissection who did not fulfill clinical criteria for MFS (Brautbar A et al. Am J Med Genet A. 2010;152A(2):413-6). In another family, this alteration was identified three individuals reported to have aortic aneurysm or dissection (Regalado ES at al. Clin Genet. 2016;89(6):719-23). This variant was previously reported in the SNPDatabase as rs193922205. It was not reported in population based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP), Exome Aggregation Consortium (ExAC) and 1000 Genomes Project. In the ESP, this variant was not observed in 6494 samples (12988 alleles) with coverage at this position. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001843461	SCV004564426	likely pathogenic	not provided	2023-02-14	criteria provided, single submitter	clinical testing	The FBN1 c.4467T>A; p.Asn1489Lys variant (rs193922205) is reported in individuals with features of Marfan syndrome (Baetens 2011, Brautbar 2010) and is reported to segregate with thoracic aortic aneurysms and dissections (TAAD) in three affected individuals of a family (Regalado 2016). This variant is reported in ClinVar (Variation ID: 36076). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.693). The asparagine at codon 1489 is a well conserved residue of the EGF consensus sequence and is critical for calcium binding (Wu 1995). Based on available information, this variant is considered to be likely pathogenic. References: Baetens M et al. Applying massive parallel sequencing to molecular diagnosis of Marfan and Loeys-Dietz syndromes. Hum Mutat. 2011 Sep;32(9):1053-62. PMID: 21542060. Brautbar A et al. FBN1 mutations in patients with descending thoracic aortic dissections. Am J Med Genet A. 2010 Feb;152A(2):413-6. PMID: 20082464. Regalado ES et al. FBN1 variants in familial thoracic aortic aneurysms and dissections. Clin Genet. 2016 Jun;89(6):719-23. PMID: 26621581. Wu YS et al. Fibrillin domain folding and calcium binding: significance to Marfan syndrome. Chem Biol. 1995 Feb;2(2):91-7. PMID: 9383409.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000586485	SCV000058845	uncertain significance	not specified	2019-02-11	flagged submission	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Center for Medical Genetics Ghent, University of Ghent	RCV000029738	SCV000787068	uncertain significance	Marfan syndrome	2017-11-07	flagged submission	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV000755191	SCV000883020	likely pathogenic	Congenital aneurysm of ascending aorta; Acute aortic dissection	2016-01-20	no assertion criteria provided	research