ClinVar

Description

The NM_00138 c.5885A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 1962 (p.Tyr1962Cys) within a calcium binding EGF-like domain of the protein (PM1). This variant was found in a proband diagnosed who met revised Ghent criteria, which is a highly specific phenotype for Marfan syndrome (MFS) (PMID 27112580, PP4). This variant has been reported four times in ClinVar: once as likely pathogenic and three times as uncertain significance (Variation ID: 570737). At least two other probands with clinical features of MFS carry the same variant (PMID 33483583, Invitae ClinVar, PS4_Sup). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.972, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). 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, PS4_Sup, PM2_Sup, PP2, PP3, PP4