ClinVar Genomic variation as it relates to human health

This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1311 of the FBN1 protein (p.Tyr1311Asn). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 25652356). ClinVar contains an entry for this variant (Variation ID: 979123). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. This variant disrupts the p.Tyr1311 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27906200, 31131229). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Variant summary: FBN1 c.3931T>A (p.Tyr1311Asn) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251280 control chromosomes. c.3931T>A has been reported in the literature in two individuals in one family affected with clinical features of Marfan Syndrome (Baudhuin_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25652356). ClinVar contains an entry for this variant (Variation ID: 979123). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Has been reported in association with an FBN1-related phenotype (PMID: 25652356); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); This variant is associated with the following publications: (PMID: 12938084, 25652356)