ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.1551+1G>A

dbSNP: rs786204553
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169269 SCV000220569 likely pathogenic Neuronal ceroid lipofuscinosis 2 2014-07-31 criteria provided, single submitter literature only
GeneDx RCV000524081 SCV000617419 pathogenic not provided 2015-12-29 criteria provided, single submitter clinical testing The c.1551+1 G>A splice site variant in the TPP1 gene has been previously reported in an individual with cLINCL who had a second TPP1 variant on the other allele (Wang et al., 2011). This pathogenic variant destroys the canonical splice donor site in intron 12, and is expected to cause abnormal gene splicing. Additionally, different variants at the same position (c.1551+1 G>T, c.1551+1 G>C) have been reported previously in association with cLINCL (Stenson et al., 2014). Therefore, c.1551+1 G>A is considered to be a pathogenic variant.
Revvity Omics, Revvity Omics RCV000524081 SCV002022404 pathogenic not provided 2022-10-05 criteria provided, single submitter clinical testing
Invitae RCV000524081 SCV002239099 pathogenic not provided 2023-06-23 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 12 of the TPP1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs786204553, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 20820830, 26032578). ClinVar contains an entry for this variant (Variation ID: 188909). Variants that disrupt 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. This variant disrupts a region of the TPP1 protein in which other variant(s) (p.Gly535Arg) have been determined to be pathogenic (PMID: 23266810). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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