ClinVar

Description

Variant summary: TPP1 c.1424C>T (p.Ser475Leu) results in a non-conservative amino acid change located in the Peptidase S8/S53 domain (IPR000209) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. The variant allele was found at a frequency of 2.4e-05 in 251484 control chromosomes (gnomAD). c.1424C>T has been reported in the literature as a biallelic genotype in individuals affected with Neuronal Ceroid-Lipofuscinosis (e.g. Sleat_1999, Dozieres-Puyravel_2020) and refractory epilepsy with intellectual disability (e.g. Long_2019). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating the variant in Chinese Hamster Ovary cells showed that the variant had no detectable enzymatic activity (0% of wild-type) despite normal translation, post translational processing, and trafficking (Walus_2010). Five ClinVar submitters have assessed the variant since 2014: two classified the variant as likely pathogenic, and three as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.