ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.1280C>T (p.Thr427Met) (rs201034755)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000764997 SCV000896180 uncertain significance Ceroid lipofuscinosis neuronal 2; Childhood-onset autosomal recessive slowly progressive spinocerebellar ataxia 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000189787 SCV000243435 uncertain significance not provided 2017-01-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TPP1 gene. The T427M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T427M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T427M 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. Additionally, missense variants in nearby residues (Q422H, E423D, K428N) have been reported in the Human Gene Mutation Database in association with neuronal ceroid lipofuscinosis (Stenson et al., 2014). 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 the T427M variant is a pathogenic variant or a rare benign variant.
Invitae RCV000689136 SCV000816776 uncertain significance Neuronal ceroid lipofuscinosis 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 427 of the TPP1 protein (p.Thr427Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs201034755, ExAC 0.06%). This variant has not been reported in the literature in individuals with TPP1-related disease. ClinVar contains an entry for this variant (Variation ID: 207590). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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