Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000138.5(FBN1):c.7003C>T (p.Arg2335Trp)

CA016924

200100 (ClinVar)

Gene: FBN1
Condition: Marfan syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 878146ab-5406-4852-b7a0-da0c3b4eaa24
Approved on: 2022-12-01
Published on: 2022-12-01

HGVS expressions

NM_000138.5:c.7003C>T
NM_000138.5(FBN1):c.7003C>T (p.Arg2335Trp)
NC_000015.10:g.48427768G>A
CM000677.2:g.48427768G>A
NC_000015.9:g.48719965G>A
CM000677.1:g.48719965G>A
NC_000015.8:g.46507257G>A
NG_008805.2:g.223021C>T
ENST00000682170.1:n.1184C>T
ENST00000682767.1:n.300C>T
ENST00000316623.10:c.7003C>T
ENST00000674301.1:n.2169C>T
ENST00000316623.9:c.7003C>T
ENST00000559133.5:n.2372C>T
NM_000138.4:c.7003C>T

Likely Pathogenic

Met criteria codes 5
PS4_Moderate PP1_Strong PM2_Supporting PP3 PP2
Not Met criteria codes 20
PVS1 BA1 BP5 BP3 BP2 BP4 BP1 BS4 BS3 BS1 BS2 PP4 PM6 PS2 PS3 PS1 PM1 PM4 PM3 PM5

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
FBN1 VCEP
NM_00138 c.7003C>T is a missense variant in FBN1 predicted to cause a substitution of an Arginine by Tryptophan at amino acid 2335 (p.Arg2335Trp). This variant was found in a proband with isolated thoracic aortic aneurysm and dissection and segregates with disease in at least 5 affected family members (PP1_strong). It has been reported 2 times in the literature in individuals with ectopia lentis but who did not meet revised Ghent criteria for Marfan syndrome (PMID: 29357934; PMID: 12203992) (PS4_moderate). This variant is not present in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis suggest that this variant may impact the protein structure (REVEL: 0.841) (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: PP1_strong, PS4_moderate, PM2_supporting, PP2, PP3.
Met criteria codes
PS4_Moderate
Two probands, neither of whom fully met revised Ghent criteria, but both of whom have ectopia lentis (1 point per proband = 2 points total, sufficient for PS4_moderate).
PP1_Strong
Variant present in more than 5 affected family members in one family, including some fourth-degree relatives
PM2_Supporting
Variant not present in gnomad
PP3
REVEL: 0.841 (>0.750 cutoff established by FBN1 VCEP)
PP2
applicable per FBN1 VCEP due to no evidence supporting benign assertion
Not Met criteria codes
PVS1
N/A for this variant
BA1
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
BP3
N/A for FBN1
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
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
PP4
Patient has isolated thoracic aortic dissection (insufficient for PP4 application) and has strong family history of TAAD but nobody with phenotype highly specific for Marfan syndrome, PP4 is not applicable.
PM6
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
PM1
N/A for this variant
PM4
N/A for this variant
PM3
N/A for FBN1
PM5
The other aminoacid change present in the literature is classified as VUS
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