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]

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Variant: NM_000138.4(FBN1):c.7165_7166CT[1] (p.Cys2390fs)

42420 (ClinVar)

Gene: FBN1

Condition: Marfan syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 93fd1b32-0700-482d-8fb2-cda364449c28

HGVS expressions

NM_000138.4:c.7165_7166CT[1]

NM_000138.4:c.7167_7168delCT

NM_000138.4(FBN1):c.7165_7166CT[1] (p.Cys2390fs)

NM_000138.5(FBN1):c.7167_7168del (p.Cys2390fs)

Pathogenic

PM6_Supporting PS4 PVS1 PP4 PM2

BS4 BS3 BS1 BP2 PS2 PS3 PS1 BA1 PP1 PM1 PM5 PM4

Evidence Links 0

Expert Panel

FBN1 VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

FBN1 VCEP

The NM_00138 c.7165_7166, is a frameshift variant in FBN1 is predicted to result in a premature stop codon at position 2404. It is expected to cause a shift in the reading frame and likely results in an absent or disrupted protein product (PVS1). This variant was found in a proband with a diagnosis of Marfan syndrome, with thoracic aortic aneurysm, skeletal features, which is a highly specific phenotype for Marfan syndrome (internal data) (PP4). This variant, also described as c.7167_7169del2 or p.Leu2389fsX16 using alternate nomenclature, has also been described in three other probands with a clinical diagnosis of Marfan syndrome (PMID 25907466, 17657824, internal data) and in three probands suspected of having Marfan syndrome (PMID 24793577, 14695540, internal data) (PS4). The variant has been identified as a de novo occurrence in an individual with a phenotype consistent with the gene but not highly specific (PM6_Supportive). This variant has been reported 5 times in ClinVar as pathogenic (Variantion ID: 42420). This variant is not present in gnomAD (PM2_sup; 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, PM6_Supportive, PM2_Supportive, PP4

PM6_Supporting

Occurred de novo in 1 individual with a “consistent phenotype” but not highly specific. de novo with unconfirmed parental relationships.

PS4

It has been previously reported in multiple individuals with Marfan or Marfan-like syndrome (reported as c.7167_7169del2 or p.Leu2389fsX16, using alternate nomenclature; PMID: 14695540). 5.5point). This variant is listed in patients tested by clinical laboratories in the ClinVar database by Integrated Genetics, GeneDx, Partners HealthCare and the University of Ghent.

PVS1

Truncating variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843).

PP4

Internal proband meets revised Ghent criteria

PM2

Variant not been reported in presumed healthy individuals in the Genome Aggregation Database (gnomAD) or Exac.

BS4