ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.797G>A (p.Arg266Gln)

gnomAD frequency: 0.00004  dbSNP: rs757953998
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189772 SCV000243420 uncertain significance not provided 2016-10-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TPP1 gene. The R266Q variant has been reported previously in a patient with CLN2 who also harbored a second TPP1 variant; however phase was undetermined (Kousi et al., 2012). Functional studies demonstrate no conformational destabilization, indicating an unclear consequence of this variant (Pal et al., 2009). 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 R266Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000189772 SCV000628917 uncertain significance not provided 2022-06-04 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 266 of the TPP1 protein (p.Arg266Gln). This variant is present in population databases (rs757953998, gnomAD 0.01%). This missense change has been observed in individual(s) with late-infantile neuronal ceroid lipofusinosis (PMID: 22832778). 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: 207580). 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.
Ambry Genetics RCV002317663 SCV000851005 uncertain significance Inborn genetic diseases 2019-02-17 criteria provided, single submitter clinical testing The p.R266Q variant (also known as c.797G>A), located in coding exon 7 of the TPP1 gene, results from a G to A substitution at nucleotide position 797. The arginine at codon 266 is replaced by glutamine, an amino acid with highly similar properties. In a structural study of TPP1, authors concluded that this alteration caused no apparent conformational destabilization and its putative functional consequence remained unclear (Pal A, et al. J. Biol. Chem. 2009;284(6):3976-84). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002265676 SCV002548005 uncertain significance not specified 2022-05-22 criteria provided, single submitter clinical testing Variant summary: TPP1 c.797G>A (p.Arg266Gln) 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251388 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.797G>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (example, Perez-Poyato_2012). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV001275122 SCV001459946 uncertain significance Neuronal ceroid lipofuscinosis 2 2020-09-16 no assertion criteria provided clinical testing

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