ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.380G>A (p.Arg127Gln) (rs121908204)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494361 SCV000583376 pathogenic not provided 2017-06-01 criteria provided, single submitter clinical testing The c.380 G>A variant in the TPP1 gene has been reported previously in individuals with late-onset neuronal ceroid lipofuscinosis (LINCL) who had a second TPP1 variant identified (Zhong et al., 2000; Steinfeld et al., 2002). Functional studies suggest that the c.380 G>A variant results in abnormal gene splicing (Steinfeld et al., 2004). The c.380 G>A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, c.380 G>A is considered to be a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000059628 SCV000920326 likely pathogenic Ceroid lipofuscinosis neuronal 2 2018-08-13 criteria provided, single submitter clinical testing Variant summary: TPP1 c.380G>A (p.Arg127Gln) results in a conservative amino acid change located in the Peptidase S53, activation domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. As the nucleotide change corresponds to an exonic splice-region (last nucleotide of exon 4), several computational tools predict a significant impact on normal splicing: Five predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. The variant was absent in 246246 control chromosomes (gnomAD). c.380G>A has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease)(Steinfeld_2004, Zhong_2000, Worgall_2007). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal enzymatic activity. Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely pathogenic/pathogenic." Based on the evidence outlined above, the variant was classified as likely pathogenic.
UniProtKB/Swiss-Prot RCV000059628 SCV000091195 not provided Ceroid lipofuscinosis neuronal 2 no assertion provided not provided
Counsyl RCV000059628 SCV000793438 likely pathogenic Ceroid lipofuscinosis neuronal 2 2017-08-16 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.