ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.1489C>T (p.Arg497Cys)

gnomAD frequency: 0.00004  dbSNP: rs377700188
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000558562 SCV000628904 uncertain significance not provided 2022-08-23 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 497 of the TPP1 protein (p.Arg497Cys). This variant is present in population databases (rs377700188, gnomAD 0.004%). 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: 457941). 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. 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.
GeneDx RCV000558562 SCV001993030 uncertain significance not provided 2019-01-29 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Natera, Inc. RCV001834753 SCV002094801 uncertain significance Neuronal ceroid lipofuscinosis 2 2021-02-22 no assertion criteria provided clinical testing

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