Submissions for variant NM_000391.4(TPP1):c.1076-2A>G

dbSNP: rs1424116749

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000667649	SCV000792134	likely pathogenic	Neuronal ceroid lipofuscinosis 2	2017-06-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001379383	SCV001577177	pathogenic	not provided	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 8 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of neuronal ceroid lipofuscinosis (PMID: 12125808, 31283065, 33604240). This variant is also known as IVS8-2A>G. ClinVar contains an entry for this variant (Variation ID: 552401). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230565	SCV003928959	likely pathogenic	Neuronal ceroid lipofuscinosis	2023-04-26	criteria provided, single submitter	clinical testing	Variant summary: TPP1 c.1076-2A>G 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 a 3' acceptor site, and two predict the variant creates a 3' acceptor site seven nucleotides downstream, potentially leading to a frameshift. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251442 control chromosomes. c.1076-2A>G has been reported in the literature in at least two compound heterozygous individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (e.g., Espitia-Segura_2021, Mole_2001). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33604240, 11589012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.