Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003069412 | SCV003467457 | likely pathogenic | not provided | 2023-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 216 of the TPP1 protein (p.Val216Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 20820830, 31059981, 34120799, 35796208). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2154688). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TPP1 protein function. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003230767 | SCV003928958 | likely pathogenic | Neuronal ceroid lipofuscinosis | 2023-04-11 | criteria provided, single submitter | clinical testing | Variant summary: TPP1 c.646G>A (p.Val216Met) results in a conservative amino acid change located in the Sedolisin domain (IPR030400) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251256 control chromosomes (gnomAD). c.646G>A has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis and Epilepsy (example: Wang_2011, Chen_2019, and Younes_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. One laboratory submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |