ClinVar Miner

Submissions for variant NM_022445.4(TPK1):c.44-2A>G

dbSNP: rs863224237
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000195651 SCV000252399 pathogenic not provided 2013-12-26 criteria provided, single submitter clinical testing c.44-2 A>G: IVS2-2 A>G in intron 2 of the TPK1 gene (NM_022445.3). The c.44-2 A>G splice site mutation in the TPK1 gene destroys the canonical splice acceptor site in intron 2. 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. Although this mutation has not been previously reported to our knowledge, it is expected to be a pathogenic mutation. The variant is found in MITONUC-MITOP panel(s).
Invitae RCV000791491 SCV000930742 pathogenic Childhood encephalopathy due to thiamine pyrophosphokinase deficiency 2022-08-23 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 215276). Disruption of this splice site has been observed in individual(s) with clinical features of TPK1-related conditions (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 2 of the TPK1 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 TPK1 are known to be pathogenic (PMID: 22152682, 25458521).

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