The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]


Variant: NM_000138.5(FBN1):c.3557A>G (p.Tyr1186Cys)

CA392324980

495594 (ClinVar)

Gene: FBN1
Condition: Marfan syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: 40d44fc6-1e1f-408a-8694-a304f4acafde
Approved on: 2023-12-29
Published on: 2023-12-29

HGVS expressions

NM_000138.5:c.3557A>G
NM_000138.5(FBN1):c.3557A>G (p.Tyr1186Cys)
NC_000015.10:g.48487107T>C
CM000677.2:g.48487107T>C
NC_000015.9:g.48779304T>C
CM000677.1:g.48779304T>C
NC_000015.8:g.46566596T>C
NG_008805.2:g.163682A>G
ENST00000684448.1:n.2231A>G
ENST00000316623.10:c.3557A>G
ENST00000316623.9:c.3557A>G
ENST00000537463.6:c.637-12457A>G
NM_000138.4:c.3557A>G
More

Pathogenic

Met criteria codes 6
PS4 PM2_Supporting PP1 PP3 PP2 PM1
Not Met criteria codes 20
BS2 BS4 BS3 BS1 BP3 BP2 BP4 BP1 BP5 BP7 PS2 PS3 PS1 BA1 PP4 PM5 PM4 PM3 PM6 PVS1

Evidence Links 0

Expert Panel

Criteria Specification Information

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

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
FBN1 VCEP
NM_000138.5 c.3557A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by a cysteine at amino acid 1186 (p.Tyr1186Cys). It has been identified in at least five individuals with diagnoses or suspicion of Marfan syndrome including the following: a pediatric patient with bilateral ectopia lentis (EL), severe thoracic aortic aneurysm and dissection (TAAD), and a systemic score of 9; an adult patient with EL and a systemic score of 6; a patient with bilateral EL, TAAD, and systemic features; an individual reported to have Marfan syndrome without specific details provided; and an individual with bilateral EL, TAAD, retinal detachment, and systemic features (PS4; PMIDs: 31061752, 11933199; UZG, Bichat, & Invitae internal data). It was also found to segregate with Marfan syndrome in two other members of an aforementioned family (PP1; Bichat internal data). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/, v2.1.1 & v3.1.2). This variant introduces a novel cysteine residue which may impede the normal formation of critical disulfide bridges (PM1). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.974). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). 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: PS4, PM1, PP1, PP2, PP3, PM2_supporting.
Met criteria codes
PS4
5 probands worth 4.5 PS4 points (proband with MFS from Stheneur et al./Bichat internal data currently counting for PP4, and is not included in PS4 application)
PM2_Supporting
absent from gnomAD
PP1
2 segregations with Marfan syndrome (Bichat)
PP3
REVEL = 0.974; > 0.750
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
Cysteine-creating variant in cbEGF14
Not Met criteria codes
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
PM2_supporting met
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
PP3 met
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
PM2_supporting met
PP4
internal proband meeting revised Ghent criteria (Bichat); VCEP decision is to include this proband in the PS4 argument rather than PP4
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.