ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.381-2A>G

dbSNP: rs1554902052
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589489 SCV000696664 likely pathogenic Neuronal ceroid lipofuscinosis 2017-05-01 criteria provided, single submitter clinical testing Variant summary: The TPP1 c.381-2A>G (IVS4-2A>G) variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict significant impact on normal splicing-loss of canonical splicing acceptor site. ESEfinder predicts changes of binding motifs for splicing enhancers. Consistently, Xiong_2015 used computational modeling and predicted variant to induce large splicing changes. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 121164 control chromosomes. The variant of interest has reported in an affected individual with LINCL as compound heterozygote. Taken together, due to lack of clinical and functional evidence, this variant is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001860125 SCV002292037 likely pathogenic not provided 2021-07-21 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: 495859). Disruption of this splice site has been observed in individual(s) with late-infantile neuronal ceroid lipofuscinosis (PMID: 11339651). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 4 of the TPP1 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 TPP1 are known to be pathogenic (PMID: 10330339).
Counsyl RCV000670849 SCV000795760 likely pathogenic Neuronal ceroid lipofuscinosis 2 2017-11-17 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.