Variant: NM_000138.5(FBN1):c.911G>A (p.Cys304Tyr)

CA392350265

495662 (ClinVar)

Gene: FBN1

Condition: Marfan syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: f2d90f19-8926-449c-b72b-96949362b243

Approved on: 2024-08-22

Published on: 2024-08-22

HGVS expressions

NM_000138.5:c.911G>A
NM_000138.5(FBN1):c.911G>A (p.Cys304Tyr)
NC_000015.10:g.48526207C>T
CM000677.2:g.48526207C>T
NC_000015.9:g.48818404C>T
CM000677.1:g.48818404C>T
NC_000015.8:g.46605696C>T
NG_008805.2:g.124582G>A
ENST00000559133.6:c.911G>A
ENST00000674301.2:c.911G>A
ENST00000316623.10:c.911G>A
ENST00000316623.9:c.911G>A
ENST00000537463.6:c.636+11504G>A
NM_000138.4:c.911G>A

Likely Pathogenic

• Met criteria codes: PM1_Strong PM2_Supporting PP3 PP2 PP4

Expert Panel

FBN1 VCEP

Criteria Specification Information

Evidence submitted by expert panel

FBN1 VCEP

NM_000138.5(FBN1):c. 911G>A is a missense variant in FBN1 predicted to cause a substitution of cysteine by tyrosine at amino acid 304 (p.Cys304Tyr). This variant was found in a proband with classical MFS with clinical Thoracic Aortic Dissection, Ectopia Lentis and a SS=7pt (Internal data Tokyo; PP4). This variant has been reported 1 time in ClinVar as Likely pathogenic and 1 time as uncertain significance (Variation ID: 632813). This variant is not present in gnomAD (PM2_Sup; https://gnomad.broadinstitute.org/ v4.1.0). This variant affects a cysteine residue in a calcium binding EGF domain. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). The constraint z-score for missense variants affecting FBN1 is 8.2 (gnomAD v.4.1.0, PP2). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.986, PP3). 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_Strong, PM2_Sup, PP4, PP3, PP2.

Met criteria codes

• PM1_Strong: Cysteine affecting residue in cbEGF2 domain.
• PM2_Supporting: Absent in gnomAD
• PP3: REVEL score: 0.986
• PP2: Missense variant in a gene that has a low rate of benign missense variation
• PP4: Internal Data (Tokyo) : Found in a 39yo female with classical MFS with TAD, EL&SS=7pt.