Submissions for variant NM_000138.5(FBN1):c.3632_3634del (p.Phe1211del)

dbSNP: rs1555398404

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000663657	SCV004037330	likely pathogenic	Marfan syndrome	2023-09-28	reviewed by expert panel	curation	The NM_00138 c.3632_3634del is an in-frame deletion in FBN1predicted to cause a deletion of a phenylalanine at position 1211 (p.Phe1211del). This variant was found in a proband with a clinical diagnosis of Marfan syndrome (internal data, University of Ghent) (PP4). This variant was also found in a proband with ectopia lentis and an adverse aortic event and was found to segregate with the disease in two affected family members (internal data, University of Tokyo) (PP1). It has been reported in the literature in two unrelated individuals with ectopia lentis (PMID 19159394, 16222657), in one individual with a clinical diagnosis of Marfan syndrome (Ambry Genetics ClinVarentry) and in two unrelated individuals with thoracic aortic aneurysm and/or dissection (PMID 37042257, 33059708) (PS4). This variant is not present in gnomAD(PM2_sup; https://gnomad.broadinstitute.org/). This variant is located in a non-repeat region in a cbEGF-like domain of the protein (PM4). The variant in FBN1 has been reported three times in ClinVar as likely pathogenic (Variation ID: 549178). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PM4, PM2_Sup, PP1, PP4.
Centre of Medical Genetics, University of Antwerp	RCV000663657	SCV002025284	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS1, PP4
Ambry Genetics	RCV002458179	SCV002616433	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2021-08-02	criteria provided, single submitter	clinical testing	The c.3632_3634delTCT variant (also known as p.F1211del) is located in coding exon 29 of the FBN1 gene. This variant results from an in-frame TCT deletion at nucleotide positions 3632 to 3634. This results in the in-frame deletion of a phenylalanine at codon 1211. This alteration has been reported in Marfan syndrome cohorts (Arbustini E et al. Hum Mutat, 2005 Nov;26:494; Söylen B et al. Clin Genet, 2009 Mar;75:265-70; Stengl R et al. Orphanet J Rare Dis, 2020 10;15:290, as well as in an individual with a clinical diagnosis of Marfan syndrome (Ambry Internal Data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV004696970	SCV005196920	likely pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Center for Medical Genetics Ghent, University of Ghent	RCV000663657	SCV000786984	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing