Submissions for variant NM_000138.5(FBN1):c.2669G>A (p.Cys890Tyr)

dbSNP: rs1555399144

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000663566	SCV003933712	likely pathogenic	Marfan syndrome	2023-06-15	reviewed by expert panel	curation	The NM_000138 c.2669G>A variant is a missense variant in FBN1 predicted to cause a substitution of cysteine by tyrosine at amino acid position 890. This variant has not been reported in the literature but was identified at one institution as de novo in proband with ectopia lentis and a systemic score of 2 (PP4, PM6; UZG). This variant has also been reported four times in ClinVar, with two classifications of likely pathogenic and two classifications of pathogenic (Variation ID: 431935). It is not present in gnomAD v2.1.1 or 3.1.2 (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in the hybrid 2 domain; cysteine residues in the hybrid domains are believed to be important for proper protein folding (PM1). Computational prediction tools and conservation analysis support that this variant may impact the protein (PP3; REVEL = 0.926). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). Three other missense variants at the same amino acid position (p.Cys890Arg, p.Cys890Gly, p.Cys890Trp) have been identified and are classified as likely pathogenic (PM5; PMIDs: 12938084, 16222657, 20564469). 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: PM1, PM5, PM6, PM2_supporting, PP2, PP3, PP4.
GeneDx	RCV000498470	SCV000589513	pathogenic	not provided	2018-10-03	criteria provided, single submitter	clinical testing	The pathogenic C890Y variant in the FBN1 gene has not been published as a pathogenic variant, nor has it beenreported as a benign variant to our knowledge. However, different missense variants affecting the same residue(C890R, C890G, C890W) have been reported in the literature in association with Marfan syndrome and ectopia lentis(Kielty et al., 1995; Arbustini et al., 2005; Aragon-Martin et al., 2010. This variant was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. The C890Y variant is a non-conservativeamino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity,charge, size and/or other properties. This substitution occurs at a position that is conserved across species and insilico analysis predicts this variant is probably damaging to the protein structure/function. In addition, the C890Yvariant is located within the TB4 domain of the FBN1 gene and is predicted to disrupt disulfide bonding with residueC876. Furthermore, missense variants in nearby residues (A882V, C887Y, C896Y) have been reported in the HumanGene Mutation Database in association with Marfan syndrome (Stenson et al., 2014), further supporting the functionalimportance of this region of the protein. In summary, C890Y in the FBN1 gene is interpreted as a pathogenic variant.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198272	SCV001369151	likely pathogenic	Progeroid and marfanoid aspect-lipodystrophy syndrome	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002279274	SCV002566515	pathogenic	Connective tissue disorder	2021-08-19	criteria provided, single submitter	clinical testing
Center for Medical Genetics Ghent, University of Ghent	RCV000663566	SCV000786877	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing