Evidence Repository - Clinical Genome Resources

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

Link to SEPIO compliant JSON-LD document

Variant: NM_000138.5:c.7643T>A

CA392325153

Gene: FBN1

Condition: Marfan syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

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

PM2_Supporting PM1 BS4 BP4

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

FBN1 VCEP

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.

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)

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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