Submissions for variant NM_000138.5(FBN1):c.3143T>C (p.Ile1048Thr)

dbSNP: rs1555398673

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000686449	SCV000813968	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2020-01-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change leads to impaired fibrillin-1 microfibril formation (PMID: 8884270, 21784848). This variant has been reported in several individuals affected with Marfan syndrome at an early age, including one de novo occurrence (PMID: 8884270, 27625872, 21135753). This variant is also described as T3276C in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 1048 of the FBN1 protein (p.Ile1048Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine.
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV000663603	SCV000930627	pathogenic	Marfan syndrome	2019-08-01	criteria provided, single submitter	clinical testing	The p.I1048T variant is a known neonatal mutation of MFS (PMID: 19002209) and it has been reported in the ClinVar by other submitters (Variation ID: 549131). Functional studies show a change in protein microfibril formation (PMID: 8884270, 21784848). Additionally, computational results of PolyPhen2, Provean, SIFT show a deleterious/damaging effect.
Mayo Clinic Laboratories, Mayo Clinic	RCV001509496	SCV001716235	pathogenic	not provided	2019-08-11	criteria provided, single submitter	clinical testing	PS4, PS3, PM2, PP2, PP4
Centre of Medical Genetics, University of Antwerp	RCV000663603	SCV002025564	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS1, PP4
Illumina Laboratory Services, Illumina	RCV000663603	SCV002034796	pathogenic	Marfan syndrome	2021-11-17	criteria provided, single submitter	clinical testing	The FBN1 c.3143T>C (p.Ile1048Thr) variant is a missense variant that has been reported in at least three studies, in which it was found in a heterozygous state in at least nine individuals with neonatal Marfan syndrome (Sureka et al. 2014; Carande et al. 2017; Tognato et al. 2019). When parental samples were available, the variant was identified to be de novo. The p.Ile1048Thr variant is absent from the Genome Aggregation Database (versions 2.1.1. and 3.1.2) in a region of good sequencing coverage, so the variant is presumed to be rare. This variant is located in exon 26, within the region of the gene in which most variants associated with neonatal Marfan syndrome are located (Tognato et al. 2019). Kirschner et al. (2011) showed that the p.Ile1048Thr variant did not affect overall structure of the protein; however, it resulted in increased fragmentation of the protein in the presence of certain proteases, higher susceptibility for degradation by matrix metalloproteases, and impaired heparin binding. Based on the collective evidence, the p.Ile1048Thr variant is classified as pathogenic for Marfan syndrome.
Center for Medical Genetics Ghent, University of Ghent	RCV000663603	SCV000786923	pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing