Submissions for variant NM_000138.5(FBN1):c.5966G>T (p.Cys1989Phe)

dbSNP: rs1597531796

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000791241	SCV004704625	pathogenic	Marfan syndrome	2024-02-22	reviewed by expert panel	curation	The NM_00138 c.5966G>T, is a missense variant in FBN1 predicted to cause a substitution of a cysteine by phenylalanine at amino acid 1989 (p.Cys1989Phe). This variant was found in a proband diagnosed with typical Marfan syndrome (internal lab data, PP4); in this family, the variant was found to be de novo in the proband’s symptomatic mother (internal lab data, PM6). This variant has been reported three times in ClinVar: once as pathogenic, once as likely pathogenic, and once as uncertain significance (Variation ID: 638559). At least three other probands with Marfan syndrome and/or clinical features of Marfan syndrome carry the same variant (PMID 29848614, Petrovsky National Research Centre of Surgery ClinVar entry, Cologne University ClinVar entry, PS4_Mod). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/v2.1.1). This variant affects a cysteine residue in a calcium binding EGF-like domain. Cysteine residues in these domains are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.947, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_Strong, PS4_Mod, PM2_Sup, PP2, PP3, PP4.
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV000791241	SCV000929750	pathogenic	Marfan syndrome	2019-07-19	criteria provided, single submitter	clinical testing	Observed c.5966G>T variant was first evaluated in our clinical center as Likely Pathogenic with in silico method by prediction programs like NetGene2, SpliceSite Predictors, Provean and PolyPhen-2, which suggest that substitution p.Cys1989Phe will have a damaging effect (Russian journal of Medical Genetics DOI:10.15829/1560-4071-2016-10-7-14). Recent study show that c.5966G>T variant was reported in other individuals as well. This variant has been reigstered by reporters to Database of Pathogenic Variants (ID DPV:8471; DPVS:8803.1) with a supporting clinical significance citations (PMID:29848614, PMID:12938084). Additionally, FBN1 is known to be mostly intolerant to missense variants (ExAC Z score = 5.33). Based on new evidences we re-evaluate c.5966G>T (p.Cys1989Phe) variant as Pathogenic.
Ambry Genetics	RCV002352305	SCV002656497	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2017-04-28	criteria provided, single submitter	clinical testing	The p.C1989F variant (also known as c.5966G>T), located in coding exon 48 of the FBN1 gene, results from a G to T substitution at nucleotide position 5966. The cysteine at codon 1989 is replaced by phenylalanine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #30 domain. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Institute of Human Genetics, Cologne University	RCV000791241	SCV001167350	likely pathogenic	Marfan syndrome		no assertion criteria provided	clinical testing