ClinVar Miner

Submissions for variant NM_000143.3(FH):c.1108+1G>T (rs1057517734)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414171 SCV000490527 likely pathogenic not provided 2016-11-10 criteria provided, single submitter clinical testing The c.1108+1G>T splice site variant in the FH gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant destroys the canonical splice donor site in intron 7. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Based on currently available evidence, c.1108+1G>T is a strong candidate for a pathogenic variant. However, the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000556340 SCV000632433 likely pathogenic Fumarase deficiency 2018-03-06 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 of the FH 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). This variant has not been reported in the literature in individuals with a FH-related disease. ClinVar contains an entry for this variant (Variation ID: 372365). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FH are known to be pathogenic (PMID: 11865300, 21398687). 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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