ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.442+1G>C

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
All of Us Research Program, National Institutes of Health RCV004016252 SCV004830768 likely pathogenic Marfan syndrome 2023-06-26 criteria provided, single submitter clinical testing This variant causes a G to C nucleotide substitution at the +1 position of intron 5 of the FBN1 gene. Splice site prediction tools predict 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). A different variant occurring at the same position, c.442+1G>A, is known to be disease-causing (ClinVar variation ID: 546550). Loss of FBN1 gene function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV005216174 SCV005861051 likely pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2024-07-23 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. 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.

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