Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000189762 | SCV000243410 | uncertain significance | not provided | 2014-04-24 | criteria provided, single submitter | clinical testing | p.Gln158Pro (CAG>CCG): c.473 A>C in exon 5 of the TPP1 gene (NM_000391.3) The Q158P variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q158P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. A missense mutation in a nearby residue (S153P) has been reported in association with neuronal ceroid lipofuscinosis (NCL) supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the Q158P variant is damaging to the protein structure/function, and this substitution occurs at a position that is not conserved across species. Additionally, it is located within in a region that is not present in the mature form of the protein. Therefore, based on the currently available information, it is unclear whether the Q158P variant is a pathogenic mutation or a rare benign variant and is interpreted to be of uncertain significance. The variant is found in EPILEPSY panel(s). |
Illumina Laboratory Services, |
RCV001104754 | SCV001261640 | uncertain significance | Neuronal ceroid lipofuscinosis 2 | 2017-04-27 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. |
Invitae | RCV000189762 | SCV002185327 | uncertain significance | not provided | 2022-07-19 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 158 of the TPP1 protein (p.Gln158Pro). This variant is present in population databases (rs757507462, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with TPP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 207572). 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 not expected to disrupt TPP1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
Natera, |
RCV001104754 | SCV001458791 | uncertain significance | Neuronal ceroid lipofuscinosis 2 | 2020-03-17 | no assertion criteria provided | clinical testing |