Submissions for variant NM_000391.4(TPP1):c.182T>C (p.Leu61Pro)

dbSNP: rs1060502179

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002028747	SCV002289601	likely pathogenic	not provided	2021-11-30	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Leu61 amino acid residue in TPP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TPP1 protein function. This variant has not been reported in the literature in individuals affected with TPP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 61 of the TPP1 protein (p.Leu61Pro).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003120801	SCV003800750	uncertain significance	not specified	2023-01-06	criteria provided, single submitter	clinical testing	Variant summary: TPP1 c.182T>C (p.Leu61Pro) results in a non-conservative amino acid change located in the activation domain (IPR015366) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251382 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.182T>C in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as likely pathogenic, using advanced in silico modeling, and citing internal patient derived evidence for a different variant affecting the same amino acid. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.