Variant: NM_000138.5(FBN1):c.5826C>A (p.Cys1942Ter)

CA269532860

547334 (ClinVar)

Gene: FBN1

Condition: Marfan syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 76fe5b55-7709-49dc-b27d-dfa97cef8168

Approved on: 2024-02-22

Published on: 2024-02-22

HGVS expressions

NM_000138.5:c.5826C>A
NM_000138.5(FBN1):c.5826C>A (p.Cys1942Ter)
NC_000015.10:g.48445467G>T
CM000677.2:g.48445467G>T
NC_000015.9:g.48737664G>T
CM000677.1:g.48737664G>T
NC_000015.8:g.46524956G>T
NG_008805.2:g.205322C>A
ENST00000559133.6:c.5826C>A
ENST00000674301.2:c.5826C>A
ENST00000684448.1:n.4500C>A
ENST00000316623.10:c.5826C>A
ENST00000674301.1:c.825C>A
ENST00000316623.9:c.5826C>A
ENST00000537463.6:c.*1589C>A
ENST00000559133.5:c.1133C>A
NM_000138.4:c.5826C>A

Pathogenic

• Met criteria codes: PS4_Supporting PM2_Supporting PVS1 PM6_Supporting PP1 PP4

Expert Panel

FBN1 VCEP

Criteria Specification Information

Evidence submitted by expert panel

FBN1 VCEP

The NM_00138 c.5826C>A, is a nonsense variant in FBN1 expected to cause a premature stop codon and likely results in an absent or disrupted protein product (PVS1). This variant was found in a proband with infantile Marfan syndrome (MFS) and was found to be de novo without confirmation of parental relationships (internal data, PP4, PM6_Supporting). This variant has been reported 7 times in ClinVar, twice as pathogenic and five times as uncertain significance (Variantion ID: 547334). At least three other probands with clinical features of MFS carry the same variant (PMID 12068374, 22772377, Centre for Human Genetics ClinVar entry, PS4_Sup). In one family with features of MFS, including mitral valve prolapse, striae, pectus carinatum, scoliosis, striae, joint hypermobility, and wrist and thumb sign, this variant was found to segregate with disease in four affected family members (PMID 12068374, PP1). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). 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_Sup, PM2_Sup, PM6_Sup, PP1, PP4

Met criteria codes

• PS4_Supporting: 1.5 Pts
• PM2_Supporting: Absent in gnomAD
• PVS1: PTC at 1942, predicted to undergo NMD
• PM6_Supporting: 1 de novo with phenotype consistent with gene without confirmation of parental relationships
• PP1: 3 segregations in 1 family with high systemic score
• PP4: one proband with infantile MFS, de novo without confirmation of maternity/paternity