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:c.7643T>A

CA392325153

Gene: FBN1
Condition: Marfan syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: 1061a5c8-8865-40bb-a426-cd2bbe3585aa

HGVS expressions

NM_000138.5:c.7643T>A
NC_000015.10:g.48421614A>T
CM000677.2:g.48421614A>T
NC_000015.9:g.48713811A>T
CM000677.1:g.48713811A>T
NC_000015.8:g.46501103A>T
NG_008805.2:g.229175T>A
ENST00000682170.1:n.1824T>A
ENST00000682767.1:n.940T>A
ENST00000316623.10:c.7643T>A
ENST00000674301.1:n.2809T>A
ENST00000316623.9:c.7643T>A
ENST00000559133.5:n.3012T>A
NM_000138.4:c.7643T>A

Uncertain Significance

Met criteria codes 4
PM2_Supporting PM1 BS4 BP4
Not Met criteria codes 21
PS2 PS4 PS3 PS1 PP4 PP1 PP3 PP2 PVS1 BA1 PM4 PM3 PM5 BS2 BS3 BS1 PM6 BP3 BP1 BP5 BP7

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
FBN1 VCEP
NM_00138 c.7643T>A is a missense variant predicted to cause a substitution of a phenylalanine by a tyrosine at amino acid position 2548. This variant is present in 1 proband with TAAD, segregating with TAAD in 1 affected family member but not segregating in another affected family member (BS4; Universitair Ziekenhuis Antwerpen). This variant occurs at a conserved position in the consensus calcium-binding sequence in a cbEGF-like domain (PM1). It is not present in gnomAD v2.1.1 (PM2_supporting). Computational prediction and evolutionary conservation analysis tools suggest no impact to the gene (BP4; REVEL = 0.298). Due to conflicting and insufficient evidence, this variant is classified as of uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM2_supporting, BS4, BP4.
Met criteria codes
PM2_Supporting
Absent in gnomAD v2.1.1 and 3.1.2
PM1
p.Phe2548 is a calcium-binding site in cbEGF domain 40
BS4
Did not segregate in a 57yr old female with ascending aorta of 43mm; proband and variant-positive sister both with TAAD (Universitair Ziekenhuis Antwerpen)
BP4
REVEL = 0.298 (less than 0.326 threshold)
Not Met criteria codes
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
no studies in HGMD or Mastermind
PS1
no other variants at amino acid position reported in the literature
PP4
Patient only with TAA
PP1
only 1 segregation reported (Universitair Ziekenhuis Antwerpen)
PP3
BP4 applicable (REVEL = 0.298)
PP2
n/a because BP4 is applied
PVS1
inconsistent variant type
BA1
PM2_supporting is met
PM4
inconsistent variant type
PM3
n/a for FBN1
PM5
no other variants at amino acid position reported in the literature
BS2
n/a for FBN1
BS3
no studies in HGMD or Mastermind
BS1
PM2_supporting is met
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
inconsistent variant type
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
inconsistent variant type
Approved on: 2022-12-01
Published on: 2022-12-01
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