ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.1425G>A (p.Ser475=)

gnomAD frequency: 0.00005  dbSNP: rs779333902
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV001027809 SCV001190423 uncertain significance Neuronal ceroid lipofuscinosis 2; Autosomal recessive spinocerebellar ataxia 7 2021-03-30 criteria provided, single submitter clinical testing TPP1 NM_000391.3 exon 11 p.Ser475= (c.1425G>A): This variant has not been reported in the literature but is present in 0.02% (4/19954) of East Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-6636402-C-T?dataset=gnomad_r2_1). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is a silent variant and does not change the amino acid, however this variant occurs in the last base of the exon which is part of the 5' splice site; splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Invitae RCV001759924 SCV001205488 uncertain significance not provided 2022-10-05 criteria provided, single submitter clinical testing This sequence change affects codon 475 of the TPP1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TPP1 protein. This variant also falls at the last nucleotide of exon 11, which is part of the consensus splice site for this exon. This variant is present in population databases (rs779333902, gnomAD 0.02%). 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: 827992). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 RCV001759924 SCV001990618 uncertain significance not provided 2022-10-25 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Natera, Inc. RCV001827209 SCV002094808 uncertain significance Neuronal ceroid lipofuscinosis 2 2020-03-04 no assertion criteria provided clinical testing

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