Submissions for variant NM_000138.5(FBN1):c.5423-1G>C

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003802374	SCV004608968	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-08-18	criteria provided, single submitter	clinical testing	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. Disruption of this splice site has been observed in individuals with Marfan syndrome (PMID: 12203987, 17657824). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 44 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).
All of Us Research Program, National Institutes of Health	RCV004805087	SCV005424758	likely pathogenic	Marfan syndrome	2024-06-09	criteria provided, single submitter	clinical testing	This variant causes a G>C nucleotide substitution at the -1 position of intron 44 of the FBN1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with FBN1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of FBN1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.