ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.665A>G (p.Asn222Ser)

gnomAD frequency: 0.00006  dbSNP: rs372787642
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000270685 SCV000341567 uncertain significance not provided 2016-05-24 criteria provided, single submitter clinical testing
Invitae RCV000270685 SCV001417041 uncertain significance not provided 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 222 of the TPP1 protein (p.Asn222Ser). This variant is present in population databases (rs372787642, gnomAD 0.01%). 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: 287701). 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 with a positive predictive value of 95%. 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 RCV000270685 SCV001992252 uncertain significance not provided 2019-05-01 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 that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Natera, Inc. RCV001828243 SCV002094861 uncertain significance Neuronal ceroid lipofuscinosis 2 2019-11-11 no assertion criteria provided clinical testing

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