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.4255C>T

CA392317923

Gene: FBN1

Condition: Marfan syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 25a8d96f-bc8a-42e5-aa0f-2467640bf3b2

HGVS expressions

NM_000138.5:c.4255C>T

NC_000015.10:g.48472632G>A

CM000677.2:g.48472632G>A

NC_000015.9:g.48764829G>A

CM000677.1:g.48764829G>A

NC_000015.8:g.46552121G>A

NG_008805.2:g.178157C>T

ENST00000683268.1:n.222C>T

ENST00000684448.1:n.2929C>T

ENST00000316623.10:c.4255C>T

ENST00000316623.9:c.4255C>T

ENST00000537463.6:c.*18C>T

NM_000138.4:c.4255C>T

Pathogenic

PS4_Supporting PP4 PVS1 PM2_Supporting

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.4255C>T is a nonsense variant in FBN1 predicted to cause a substitution of a Glutamine by a termination codon at amino acid 1419 (p.Gln1419*), which likely results in an absent or disrupted protein product (PVS1). This variant was found in a proband with thoracic aortic aneurysm or dissection (TAAD) and a systemic score ≥7 (PMID: 29357934) (PS4_supporting). This variant was also found in an internal proband who meets the revised Ghent criteria for a diagnosis of Marfan syndrome (TAAD, systemic score ≥7) (PP4). This variant is not present in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). 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: PVS1, PS4_supporting, PM2_supporting, PP4.

PS4_Supporting

1 proband meeting revised Ghent criteria: 1 point

PP4

Internal proband meets revised Ghent criteria (TAD, systemic score >7)

PVS1

Nonsense variant resulting in a premature truncation and is not expected to escape nonsense-mediated decay due to location in exon 34/65

PM2_Supporting

Variant is absent from controls

Approved on: 2022-12-01

Published on: 2022-12-01

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.