Variant: NM_000138.5(FBN1):c.8080C>T (p.Arg2694Ter)

CA017544

163461 (ClinVar)

Gene: FBN1

Condition: Marfan syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 83c08467-6b08-4c83-98b3-504c8959129d

HGVS expressions

NM_000138.5:c.8080C>T
NM_000138.5(FBN1):c.8080C>T (p.Arg2694Ter)
NC_000015.10:g.48412715G>A
CM000677.2:g.48412715G>A
NC_000015.9:g.48704912G>A
CM000677.1:g.48704912G>A
NC_000015.8:g.46492204G>A
NG_008805.2:g.238074C>T
ENST00000682158.1:n.1461C>T
ENST00000682170.1:n.2261C>T
ENST00000682767.1:n.1377C>T
ENST00000316623.10:c.8080C>T
ENST00000674301.1:c.3246C>T
ENST00000316623.9:c.8080C>T
ENST00000559133.5:c.3449C>T
ENST00000561429.1:n.335C>T
NM_000138.4:c.8080C>T

Pathogenic

• Met criteria codes: PVS1 PM2_Supporting PM6

Expert Panel

FBN1 VCEP

Criteria Specification Information

Evidence submitted by expert panel

FBN1 VCEP

The NM_00138 c.8080C>T, is a nonsense variant in FBN1 which is predicted to result in a premature stop codon at position 2694, and likely results in an absent or disrupted protein product (PVS1). This variant was found in a proband with thoracic aortic aneurysm, ectopia lentis, and a systemic score of 10, which is a highly specific phenotype for Marfan syndrome (internal data) (PP4). The variant has been identified as a de novo occurrence, without confirmation of paternity and maternity, in one individual with highly specific phenotype and in one individual with a phenotype consistent with the gene but not highly specific (Internal data- Bichat) (PM6). This variant was also found in a proband with ectopia lentis, thoraic aortic aneurysm, and skeletal features, and was found to segregate with the disease in 1 affected family member (internal data, John Hopkins). This variant has been reported 9 times in ClinVaras pathogenic (Variation ID: 163461). At least 20 other probands with a clinical diagnosis of Marfan syndrome and/or clinical features of Marfan syndrome carry the same variant (PMID 17680538, 19293843, 19839986, 24199744, 26787436, 14695540, 18435798, 26133393, internal data, PS4). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). 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, PM6, PM2_Sup, PP4.

Met criteria codes

• PVS1: within second last exon, not last 50 bp
• PM2_Supporting: 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

Approved on: 2023-09-28

Published on: 2023-09-28