Submissions for variant NM_000138.5(FBN1):c.6616+1G>A

dbSNP: rs1064793980

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482028	SCV000567500	pathogenic	not provided	2016-04-07	criteria provided, single submitter	clinical testing	The c.6616+1 G>A variant has been reported previously in two individuals with Marfan syndrome(Attanasio et al., 2008; Proost et al., 2015). This variant destroys the canonical splice donor site inintron 54 and is predicted to cause abnormal gene splicing. This variant is predicted to lead to eitheran abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal proteinproduct if the message is used for protein translation. Other splice site variants in the FBN1 gene,including two affecting the same splice donor site (c.6616+1 G>T; c.6616+2 T>A), have beenreported in HGMD in association with Marfan syndrome (Stenson et al., 2014). Furthermore, thec.6616+1 G>A variant was not observed in approximately 6,500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benignvariant in these populations. In summary, c.6616+1 G>A in the FBN1 gene is interpreted as a pathogenic variant.
Invitae	RCV000808422	SCV000948531	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2021-11-11	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 419595). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individual(s) with Marfan syndrome (PMID: 19293843, 25907466). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 54 of the FBN1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843).
Centre of Medical Genetics, University of Antwerp	RCV000663884	SCV002025402	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS7, PP4
Center for Medical Genetics Ghent, University of Ghent	RCV000663884	SCV000787249	pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing