Submissions for variant NM_000138.5(FBN1):c.6453C>T (p.Cys2151=)

dbSNP: rs794728251

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000576722	SCV004037320	pathogenic	Marfan syndrome	2023-09-28	reviewed by expert panel	curation	The NM_000138.5 c.6453C>T variant in FBN1does not result in an amino acid substitution. This variant was found in a proband with thoracic aortic aneurysm and/or dissection, and a systemic score of 8, which is a highly specific phenotype for Marfan syndrome (internal data-Ghent university Hospital) (PP4). This variant has been reported 6 times in ClinVar: 4 times as pathogenic, 2 times as likely pathogenic, and once as variant of uncertain significance (Variation ID: 200193). The variant has been reported in the literature in at least two unrelated individuals with a clinical diagnosis of Marfan syndrome, and in at least four unrelated individuals with clinical features of Marfan syndrome (PMID 26787436, 36517271, 21907952, 32679894, 36517271, InvitaeClinVarentry) (PS4). This variant was also found to segregate with disease in at least 5 affected relatives from multiple families (PMID 21907952, internal data) (PP1_Strong). In silico prediction programs predict that this variant may impact splicing (PP3). RNA functional studies confirmed that this variant results in the creation of a cryptic donor splice site resulting in an abnormal truncated protein (PMID 21907952, 26787436, 32123317) (PS3). 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: PS3, PS4, PP1_Strong, PM2_Sup, PP3, PP4
GeneDx	RCV000505798	SCV000234003	pathogenic	not provided	2023-03-09	criteria provided, single submitter	clinical testing	Published functional studies revealed a truncated mRNA product due to the creation of a new cryptic splice donor site for intron 53 (Ogawa et al., 2011; Wai et al., 2020); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32679894, 32123317, 21907952, 26787436)
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000576722	SCV000678202	likely pathogenic	Marfan syndrome	2017-08-01	criteria provided, single submitter	clinical testing	FBN1 NM_000138.4 exon 53 p.Cys2151Cys (c.6453C>T): This variant has been reported in the literature in 1 individual with Marfan syndrome, segregating with disease in 2 affected relatives (Ogawa 2011 PMID:21907952). This variant is not present in large control databases. Although this is a ‘silent’ mutation, functional studies have demonstrated that this variant may result in a splice site alteration, resulting in an abnormal protein (Ogawa 2011 PMID:21907952). In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic.
Invitae	RCV000631984	SCV000753087	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change affects codon 2151 of the FBN1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FBN1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of Marfan syndrome (PMID: 21907952, 26787436, 32679894; Invitae). ClinVar contains an entry for this variant (Variation ID: 200193). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000505798	SCV000885426	pathogenic	not provided	2017-07-30	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000505798	SCV001449867	pathogenic	not provided	2016-08-18	criteria provided, single submitter	clinical testing
Center for Medical Genetics Ghent, University of Ghent	RCV000576722	SCV000787233	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing