ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs786204553
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411444 SCV000485467 likely pathogenic Neuronal ceroid lipofuscinosis 2 2015-12-15 criteria provided, single submitter clinical testing
Invitae RCV001038809 SCV001202305 pathogenic not provided 2023-08-10 criteria provided, single submitter clinical testing Disruption of this splice site has been observed in individual(s) with late infantile neuronal ceroid lipofuscinosis (PMID: 20820830, 23374165, 26032578). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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. ClinVar contains an entry for this variant (Variation ID: 370214). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the TPP1 protein in which other variant(s) (p.Trp542*) have been determined to be pathogenic (PMID: 31283065; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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.
GeneDx RCV001038809 SCV004021465 likely pathogenic not provided 2023-01-18 criteria provided, single submitter clinical testing Observed in a patient with neuronal ceroid lipofuscinosis; however, no further clinical information was provided (Santorelli et al., 2013); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23374165)

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