Submissions for variant NM_000138.5(FBN1):c.2677+1G>A

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003783659	SCV004570932	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-05-09	criteria provided, single submitter	clinical testing	Disruption of this splice site has been observed in individual(s) with Marfan syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 22 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004723467	SCV005337786	pathogenic	FBN1-related disorder	2024-06-11	no assertion criteria provided	clinical testing	The FBN1 c.2677+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in an individual with Marfan syndrome (supplementary data, Groth et al. 2017. PubMed ID: 27906200). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant has been interpreted as likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/2925565/). Variants that disrupt the consensus splice donor site in FBN1 are expected to be pathogenic. This variant is interpreted as pathogenic.