ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.89+5G>C (rs746085696)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189799 SCV000243447 pathogenic not provided 2013-06-27 criteria provided, single submitter clinical testing c.89+5 G>C: IVS2+5 G>C in intron 2 of the TPP1 gene (NM_000391.3)The c.89+5 G>C substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. Multiple in silico splice prediction models indicate that this mutation destroys the normal splice donor site in intron 2, causing abnormal gene splicing. Therefore, c.89+5 G>C is considered a disease-causing mutation. The variant is found in EPILEPSY panel(s).
Invitae RCV000796045 SCV000935536 pathogenic Neuronal ceroid lipofuscinosis 2019-08-28 criteria provided, single submitter clinical testing This sequence change falls in intron 2 of the TPP1 gene. It does not directly change the encoded amino acid sequence of the TPP1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with neuronal ceroid lipofuscinosis in a family and is present in an additional individual with clinical features of neuronal ceroid lipofuscinosis (PMID: 23266810, Invitae). ClinVar contains an entry for this variant (Variation ID: 207599). Nucleotide substitutions within 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 disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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