ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.6164-2A>G (rs794728244)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414307 SCV000491648 pathogenic not provided 2016-11-09 criteria provided, single submitter clinical testing Although the c.6164-2 A>G variant has not been reported as a pathogenic variant or as a benign variant to ourknowledge, it destroys the canonical splice acceptor site in intron 50 and is predicted to cause abnormal genesplicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNAdecay, or to an abnormal protein product if the message is used for protein translation. Other downstream splice sitevariants in the FBN1 gene and a different pathogenic splice site variant affecting the same nucleotide (c.6164-2 A>T)have been reported in HGMD or at GeneDx in association with Marfan syndrome (Stenson et al., 2014). Furthermore,the c.6164-2 A>G variant was not observed in approximately 6,500 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in thesepopulations.In summary, c.6164-2 A>G in the FBN1 gene is interpreted as a pathogenic variant.
Invitae RCV000470995 SCV000544923 likely pathogenic Marfan syndrome 2016-10-01 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 50 of the FBN1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FBN1-related disease. In summary, donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547), and loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic.

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