ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.4337-3A>C

gnomAD frequency: 0.00002  dbSNP: rs770551687
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001179385 SCV000319333 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2014-11-19 criteria provided, single submitter clinical testing The c.4337-3A>C intronic variant results from an A to C substitution 3 nucleotides upstream from coding exon 35 in the FBN1 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6,494 samples (12,988 alleles) with coverage at this position. This nucleotide position is well conserved in available vertebrate species, though the C allele is present in wallaby and platypus. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on the native splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health RCV001179385 SCV001344039 likely benign Familial thoracic aortic aneurysm and aortic dissection 2019-01-11 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001859451 SCV002221444 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2021-11-26 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 263868). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. This variant is present in population databases (rs770551687, gnomAD 0.01%). This sequence change falls in intron 35 of the FBN1 gene. It does not directly change the encoded amino acid sequence of the FBN1 protein. It affects a nucleotide within the consensus splice site.
All of Us Research Program, National Institutes of Health RCV003995692 SCV004830891 likely benign Marfan syndrome 2023-06-26 criteria provided, single submitter clinical testing

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