Variant: NM_000138.5(FBN1):c.4583-5A>G

CA16614422

406332 (ClinVar)

Gene: FBN1

Condition: Marfan syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 73ca8855-9682-4983-8b82-6adb0367e0ef

Approved on: 2023-06-15

Published on: 2023-06-15

HGVS expressions

NM_000138.5:c.4583-5A>G
NM_000138.5(FBN1):c.4583-5A>G
NC_000015.10:g.48468107T>C
CM000677.2:g.48468107T>C
NC_000015.9:g.48760304T>C
CM000677.1:g.48760304T>C
NC_000015.8:g.46547596T>C
NG_008805.2:g.182682A>G
ENST00000559133.6:c.4583-5A>G
ENST00000674301.2:c.4583-5A>G
ENST00000684448.1:n.3257-5A>G
ENST00000316623.10:c.4583-5A>G
ENST00000316623.9:c.4583-5A>G
ENST00000537463.6:c.*346-5A>G
NM_000138.4:c.4583-5A>G

Likely Pathogenic

• Met criteria codes: PM6_Supporting PP3 PP4 PS4_Moderate PM2_Supporting

• Not Met criteria codes: PVS1 PS1 PS2 PS3 BA1 PP1 PP2 PM1 PM3 PM5 PM4 BS1 BS4 BS3 BS2 BP5 BP7 BP4 BP3 BP1 BP2

Expert Panel

FBN1 VCEP

Criteria Specification Information

Criteria Specification: ClinGen FBN1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Evidence submitted by expert panel

FBN1 VCEP

The NM_000138.5 c.4583-5A>G variant in FBN1 is a variant in the splice acceptor region of intron 37. Computational splice prediction algorithms predict that this variant impacts splicing (PP3). This variant was identified in the literature and public databases in two individuals with clinical diagnoses of Marfan syndrome including once as de novo in an individual with phenotype consistent with but not highly specific to FBN1 and in an individual with aortic aneurysm and other features suggestive of Marfan syndrome; it was also found to segregate with disease in at least one affected family member (PS4_moderate, PM6_supporting; PMID: 25101912, Invitae internal data, ClinVar ID: 406332). It was also identified in a third individual with a clinical diagnosis of Marfan syndrome (PP4; Johns Hopkins). This variant is not present in gnomAD v2.1.1 or v3.1.2 (PM2_supporting; https://gnomad.broadinstitute.org/). 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 (PS4_moderate, PM2_supporting, PM6_supporting, PP3, PP4).

Met criteria codes

• PM6_Supporting: 1 proband (Baudhuin et al) identified to have this variant as de novo (mat/pat not confirmed) with consistent but not highly specific phenotype
• PP3: GeneSplicer, MaxEntscan, and NNSPLICE all predict addition/strengthening of cryptic acceptor site, and weakening of canonical acceptor site; SpliceAI score for Acceptor Gain = 0.99
• PP4: 1 internal proband who meets revised Ghent criteria (Johns Hopkins)
• PS4_Moderate: 2 probands who meet revised Ghent criteria, 1 with TAAD + skeletal features; 2.5 PS4 points
• PM2_Supporting: not present in gnomAD v2.1.1 or v3.1.2

Not Met criteria codes

• PVS1: n/a
• PS1: n/a
• PS2: no evidence
• PS3: no evidence
• BA1: PM2_supporting
• PP1: only 1 segregation
• PP2: n/a
• PM1: n/a
• PM3: n/a for FBN1
• PM5: n/a
• PM4: n/a
• BS1: PM2_supporting
• BS4: no evidence
• BS3: no evidence
• BS2: n/a for FBN1
• BP5: no evidence
• BP7: n/a
• BP4: PP3 met
• BP3: n/a for FBN1
• BP1: n/a for FBN1
• BP2: no evidence