Submissions for variant NM_000138.5(FBN1):c.7330+3_7330+6del

dbSNP: rs1597516325

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV003330093	SCV004037329	likely pathogenic	Marfan syndrome	2023-09-26	reviewed by expert panel	curation	NM_000138.5 c.7330+3_7330+6del is an intronic variant that removes 4 nucleotides in a splice region. Computational prediction tools strongly suggest that this variant weakens or eliminates use of the canonical donor splice site in intron 58 (PP3). This variant was identified in an internal proband who met the revised Ghent criteria for Marfan syndrome with TAAD and a systemic score of 11 (PP4; University of Tokyo). This variant has been reported in the literature and in ClinVar (Variation ID: 636961) in at least 4 unrelated individuals with clinical suspicion of Marfan syndrome (PS4_moderate; PMID: 19839986, GeneDx, Blueprint Genetics). In one of these cases, the variant was found to be de novo with confirmed parentage in an individual with skeletal features and striae, a non-specific phenotype with high genetic heterogeneity (PS2_supporting; GeneDx). In another family, this variant was found to segregate with features or a diagnosis of Marfan syndrome in 3 affected family members (PP1; GeneDx). This variant is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4_moderate, PS2_supporting, PM2_supporting, PP1, PP3, PP4).
Blueprint Genetics	RCV000788937	SCV000928235	likely pathogenic	not provided	2019-02-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000788937	SCV002525237	pathogenic	not provided	2022-06-02	criteria provided, single submitter	clinical testing	Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19839986)
Ambry Genetics	RCV002386368	SCV002668844	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-11-09	criteria provided, single submitter	clinical testing	The c.7330+3_7330+6delAAGT intronic variant, located in intron 58 of the FBN1 gene, results from a deletion of 4 nucleotides within intron 58 of the FBN1 gene. This variant has been reported in an individual from a Marfan syndrome cohort; however, clinical details were limited (Hung CC et al. Ann Hum Genet, 2009 Nov;73:559-67). This nucleotide region is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.