ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.509-1G>T (rs56144125)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000391641 SCV000330101 pathogenic not provided 2015-12-31 criteria provided, single submitter clinical testing The c.509-1 G>T pathogenic variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.509-1 G>T splice site variant in the TPP1 gene destroys the canonical splice acceptor site in intron 5. 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. Additionally, variants at the same canonical splice acceptor site have been reported in Human Gene Mutation Database in association with late-infantile neuronal ceroid lipofuscinosis (Stenson et al., 2014). Therefore, c.509-1 G>T is considered to be a pathogenic variant.
Counsyl RCV000666428 SCV000790719 likely pathogenic Ceroid lipofuscinosis neuronal 2 2017-04-06 criteria provided, single submitter clinical testing
Invitae RCV001209638 SCV001381083 pathogenic Neuronal ceroid lipofuscinosis 2019-07-23 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the TPP1 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). Disruption of this splice site has been observed in individuals affected with neuronal ceroid lipofuscinosis (PMID: 10330339). ClinVar contains an entry for this variant (Variation ID: 280202). 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 TPP1 are known to be pathogenic (PMID: 10330339). For these reasons, this variant has been classified as Pathogenic.

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