ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.1048C>T (p.Arg350Trp)

dbSNP: rs1554901784
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668234 SCV000792805 uncertain significance Neuronal ceroid lipofuscinosis 2 2017-07-17 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001058281 SCV001222839 pathogenic not provided 2023-11-10 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 350 of the TPP1 protein (p.Arg350Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis type 2 (PMID: 23266810). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 552886). 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%. For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000668234 SCV002519892 pathogenic Neuronal ceroid lipofuscinosis 2 2022-05-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003117472 SCV003800751 likely pathogenic Neuronal ceroid lipofuscinosis 2023-01-12 criteria provided, single submitter clinical testing Variant summary: TPP1 c.1048C>T (p.Arg350Trp) results in a non-conservative amino acid change located in the Peptidase S8/S53 domain (IPR000209) and Sedolisin domain (IPR030400) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251346 control chromosomes. c.1048C>T has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) with co-segregation data providing strong evidence for causality (e.g. Kohan_2013, Chen_2019, Gardner_2019, Lourenco_2020, Guelbert_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments; two submitters cite the variant as pathogenic, and two submitters cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Natera, Inc. RCV000668234 SCV002094832 uncertain significance Neuronal ceroid lipofuscinosis 2 2021-02-03 no assertion criteria provided clinical testing

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