Variant: NM_000138.5(FBN1):c.3457T>C (p.Cys1153Arg)

CA10587839

263660 (ClinVar)

Gene: FBN1

Condition: Marfan syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 8da1a8d1-c54e-4570-a684-4e53ecee49bb

Approved on: 2023-12-29

Published on: 2023-12-29

HGVS expressions

NM_000138.5:c.3457T>C
NM_000138.5(FBN1):c.3457T>C (p.Cys1153Arg)
NC_000015.10:g.48487318A>G
CM000677.2:g.48487318A>G
NC_000015.9:g.48779515A>G
CM000677.1:g.48779515A>G
NC_000015.8:g.46566807A>G
NG_008805.2:g.163471T>C
ENST00000684448.1:n.2131T>C
ENST00000316623.10:c.3457T>C
ENST00000316623.9:c.3457T>C
ENST00000537463.6:c.637-12668T>C
NM_000138.4:c.3457T>C

Likely Pathogenic

• Met criteria codes: PM2_Supporting PM1_Strong PP3 PP2

• Not Met criteria codes: PM5

Expert Panel

FBN1 VCEP

Criteria Specification Information

Evidence submitted by expert panel

FBN1 VCEP

The NM_00138 c.3457T>C, is a missense variant in FBN1 predicted to cause a substitution of a cysteine residue by arginine at amino acid 1153 (p.Cys1153Arg) in a calcium binding EGF-like domain. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). This variant has been reported two times in ClinVar: once as likely pathogenic, and once as uncertain significance (Variation ID: 263660). To our knowledge, this variant has not previously been reported in individuals affected with Marfan syndrome in the literature. This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). Other missense variants affecting the same residue, including p.Cys1153Ser, Cys1153Phe, and Cys1153Tyr, have been previously reported in individuals with Marfan syndrome (PMID 16222657, 14695540, 24928929, internal data). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.944, 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_Strong, PM2_Sup, PP2, PP3.

Met criteria codes

• PM2_Supporting: Absent in GnomAD v2.1.1
• PM1_Strong: Removing Cys residue in a calcium binding EGF-like domain
• PP3: REVEL: 0.944 (Threshold: >0.75)
• PP2: z-score is 5.06

Not Met criteria codes

• PM5: PM1_Strong applied