The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
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  • No CSPEC computed assertion could be determined for this classification!

  • See Evidence submitted by expert panel for details.

Variant: NM_000138.5(FBN1):c.3650G>A (p.Gly1217Asp)

CA392324483

549180 (ClinVar)

Gene: FBN1
Condition: Marfan syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: 4a8d3506-3393-401b-b56e-a28a50410118
Approved on: 2024-05-23
Published on: 2024-10-31

HGVS expressions

NM_000138.5:c.3650G>A
NM_000138.5(FBN1):c.3650G>A (p.Gly1217Asp)
NC_000015.10:g.48485436C>T
CM000677.2:g.48485436C>T
NC_000015.9:g.48777633C>T
CM000677.1:g.48777633C>T
NC_000015.8:g.46564925C>T
NG_008805.2:g.165353G>A
ENST00000559133.6:c.3650G>A
ENST00000674301.2:c.3650G>A
ENST00000684448.1:n.2324G>A
ENST00000316623.10:c.3650G>A
ENST00000316623.9:c.3650G>A
ENST00000537463.6:c.637-10786G>A
NM_000138.4:c.3650G>A
More

Likely Pathogenic

Met criteria codes 6
PP4 PP3 PP2 PM1 PS4_Moderate PM2_Supporting
Not Met criteria codes 16
BP5 BP2 BP4 BP1 PS2 PS3 PS1 PP1 PM3 PM5 PM6 BA1 BS4 BS3 BS1 BS2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
FBN1 VCEP
The NM_00138 c.3650G>A is a missense variant in FBN1 predicted to cause a substitution of a glycine by aspartic acid at amino acid 1217 (p.Gly1217Asp). This cysteine-creating variant impacts a critical glycine between Cys3 and Cys4 within a calcium binding EGF-like domain, important for interdomain packaging (PM1, PMID 31227806). This variant was found in a pediatric proband with a systemic score >7 and thoracic aortic dissection, which is a highly specific phenotype for Marfan syndrome (MFS) (internal lab data, PP4). In this family, the variant was found to be inherited from the probands affected father (internal lab data). This variant has been reported three times in ClinVar: once as likely pathogenic, and twice as uncertain significance (Variation ID: 549180). This variant has also been reported in at least 4 individuals with a clinical diagnosis of MFS or clinical features of MFS (PS4_Mod; PMID 27112580, Petrovsky National Research Centre of Surgery ClinVar entry, Internal lab data). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.987, 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, PS4_Mod, PM2_Sup, PP2, PP3, PP4.
Met criteria codes
PP4
1 pediatric individual with Systemic score >7 and thoracic aortic disease
PP3
REVEL score: 0.869
PP2
Missense variant
PM1
Gly between Cys3-Cys4 if there is an upstream cbEGF domain
PS4_Moderate
3 points
PM2_Supporting
Absent in gnomAD
Not Met criteria codes
BP5
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
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
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
PP1
Internal lab data: 1 pediatric individual with SS>7 and TAD; inherited from affected father
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
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
BA1
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
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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