Submissions for variant NM_000391.4(TPP1):c.1424C>T (p.Ser475Leu)

gnomAD frequency: 0.00002  dbSNP: rs121908202

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000059623	SCV000790555	likely pathogenic	Neuronal ceroid lipofuscinosis 2	2017-03-28	criteria provided, single submitter	clinical testing
Invitae	RCV000800616	SCV000940342	pathogenic	not provided	2023-08-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPP1 function (PMID: 20340139). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 68741). This missense change has been observed in individual(s) with TPP1-related conditions (PMID: 10330339, 21990111, 23266810). This variant is present in population databases (rs121908202, gnomAD 0.01%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 475 of the TPP1 protein (p.Ser475Leu).
GeneDx	RCV000800616	SCV001818976	pathogenic	not provided	2019-12-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the S475L variant results in no measurable TPP1 activity compared to wild type (Walus et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 31216804, 31283065, 31059981, 31139143, 25976102, 19246452, 15965709, 10477428, 11054422, 10330339, 19038966, 20340139, 21990111, 23266810)
Revvity Omics, Revvity	RCV000800616	SCV002020274	likely pathogenic	not provided	2021-09-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307388	SCV002600335	pathogenic	Neuronal ceroid lipofuscinosis	2022-10-07	criteria provided, single submitter	clinical testing	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.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000059623	SCV003915842	pathogenic	Neuronal ceroid lipofuscinosis 2	2023-04-13	criteria provided, single submitter	clinical testing	A Homozygous missense variation in exon 11 of the TPP1 gene that results in the amino acid substitution of Leucine for Serine at codon 475 was detected. The observed variant c.1424C>T (p.Ser475Leu) has not been reported in the 1000 genomes and has a MAF of 0.0024% in the gnomAD databases. The in silico prediction of the variant are possibly damaging by PolyPhen-2, SIFT, FATHMM and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.
UniProtKB/Swiss-Prot	RCV000059623	SCV000091190	not provided	Neuronal ceroid lipofuscinosis 2		no assertion provided	not provided
Natera, Inc.	RCV000059623	SCV001455826	pathogenic	Neuronal ceroid lipofuscinosis 2	2020-09-16	no assertion criteria provided	clinical testing