Submissions for variant NM_000391.4(TPP1):c.1222_1224del (p.Ser408del)

gnomAD frequency: 0.00001  dbSNP: rs1474804613

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001862794	SCV002168747	pathogenic	not provided	2025-01-06	criteria provided, single submitter	clinical testing	This variant, c.1222_1224del, results in the deletion of 1 amino acid(s) of the TPP1 protein (p.Ser408del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 31216804; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 846307). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001862794	SCV003820953	uncertain significance	not provided	2019-08-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800673	SCV005423473	likely pathogenic	Neuronal ceroid lipofuscinosis	2024-10-03	criteria provided, single submitter	clinical testing	Variant summary: TPP1 c.1222_1224delAGT (p.Ser408del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 4e-06 in 251460 control chromosomes (gnomAD). c.1222_1224delAGT has been reported in the literature in compound heterozygous and homozygous individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) or progressive myoclonic epilepsy (Prez-Poyato_2012, Zhang_2019, Ganapathy_2019, Niu_2022). These data indicate that the variant is likely to 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: 31069529, 36034301, 22832778, 31216804). ClinVar contains an entry for this variant (Variation ID: 846307). Based on the evidence outlined above, the variant was classified as likely pathogenic.