ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.775C>T (p.Arg259Cys)

gnomAD frequency: 0.00001  dbSNP: rs748038934
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001662760 SCV000822960 uncertain significance not provided 2022-10-24 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 259 of the TPP1 protein (p.Arg259Cys). This variant is present in population databases (rs748038934, gnomAD 0.005%). 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: 572977). 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 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 RCV001662760 SCV001873996 uncertain significance not provided 2021-08-23 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002406589 SCV002672185 uncertain significance Inborn genetic diseases 2018-02-28 criteria provided, single submitter clinical testing The p.R259C variant (also known as c.775C>T), located in coding exon 7 of the TPP1 gene, results from a C to T substitution at nucleotide position 775. The arginine at codon 259 is replaced by cysteine, an amino acid with highly dissimilar properties. 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.
Natera, Inc. RCV001830522 SCV002094856 uncertain significance Neuronal ceroid lipofuscinosis 2 2019-11-11 no assertion criteria provided clinical testing

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