Submissions for variant NM_000391.4(TPP1):c.1146-1G>A

dbSNP: rs1131691676

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494500	SCV000582612	likely pathogenic	not provided	2018-11-13	criteria provided, single submitter	clinical testing	The c.1146-1 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It 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.1146-1 G>A splice site variant in the TPP1 gene destroys the canonical splice acceptor site in intron 9. 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. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003403142	SCV004122844	likely pathogenic	Neuronal ceroid lipofuscinosis	2023-10-13	criteria provided, single submitter	clinical testing	Variant summary: TPP1 c.1146-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site and two predict the variant also strengthens a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250238 control chromosomes (gnomAD). c.1146-1G>A has been reported in the literature in the homozygous state in an individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Ganapathy_2019). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31069529). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Natera, Inc.	RCV001829413	SCV002094824	likely pathogenic	Neuronal ceroid lipofuscinosis 2	2021-01-13	no assertion criteria provided	clinical testing