Variant: NM_000138.5:c.4149_4154del

CA915940949

Gene: FBN1

Condition: Marfan syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: e49d82e2-1bb3-4b2e-a018-5f4410263915

Approved on: 2022-12-01

Published on: 2022-12-01

HGVS expressions

NM_000138.5:c.4149_4154del
NC_000015.10:g.48474311_48474316del
CM000677.2:g.48474311_48474316del
NC_000015.9:g.48766508_48766513del
CM000677.1:g.48766508_48766513del
NC_000015.8:g.46553800_46553805del
NG_008805.2:g.176473_176478del
ENST00000684448.1:n.2823_2828del
ENST00000316623.10:c.4149_4154del
ENST00000316623.9:c.4149_4154del
ENST00000537463.6:c.821_826del
NM_000138.4:c.4149_4154del

Pathogenic

• Met criteria codes: PM2_Supporting PM1 PM4 PS2 PP4

• Not Met criteria codes: PVS1 BS2 BS3 BS1 BP4 BP1 BP3 PM3 PM6 PS3 PS4 BA1 PP3 PP2

Expert Panel

FBN1 VCEP

Criteria Specification Information

Evidence submitted by expert panel

FBN1 VCEP

NM00138 c.4149_4154del is a deletion predicted to remove the methionine and glycine at amino acid positions 1384 and 1385, respectively, but is not expected to impact the reading frame (PM4). This variant was found to be confirmed as de novo in a young child with a clinical diagnosis of Marfan syndrome (PP4 and PS2; Universitair Ziekenhuis Antwerpen). This variant is not present in gnomAD v2.1.1 (PM2_supporting). p.Gly1385 is known to be involved in interdomain packaging of the protein, and its deletion may disrupt protein structure and/or function (PM1). This variant has not been reported in the published literature or public databases. In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS2, PM1, PM4, PP4, PM2_supporting.

Met criteria codes

• PM2_Supporting: absent from gnomAD v2.1.1 and v3.1.2
• PM1: Deletion of p.Gly1385 (interdomain packaging)
• PM4: in-frame deletion of 2 amino acids
• PS2: One proband with aortic dilatation + features of a connective tissue disorder (UZA)- confirmed de novo
• PP4: One proband with Marfan syndrome (UZA)

Not Met criteria codes

• PVS1: n/a - variant type
• BS2: n/a for FBN1
• BS3: no publications in HGMD or Mastermind
• BS1: PM2_supporting met
• BP4: not missense, no predicted impact to splicing
• BP1: n/a for FBN1
• BP3: n/a for FBN1
• PM3: n/a for FBN1
• PM6: PS2 met
• PS3: no publications in HGMD or Mastermind
• PS4: no publications in HGMD or Mastermind
• BA1: PM2_supporting met
• PP3: not missense, no predicted impact to splicing
• PP2: n/a - variant type