ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.379C>T (p.Arg127Ter) (rs756564767)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189759 SCV000243407 pathogenic not provided 2018-06-22 criteria provided, single submitter clinical testing The R127X nonsense variant in the TPP1 gene has been reported previously in the homozygous and compound heterozygous state in multiple unrelated individuals with neuronal ceroid lipofuscinosis (Sleat et al., 1999; Kousi et al., 2012; Di Fruscio et al., 2015). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R127X variant is observed in 11/34420 (0.03%) alleles from individuals of Latino background (Lek et al., 2016). Therefore, we interpret R127X as a pathogenic variant.
Fulgent Genetics,Fulgent Genetics RCV000763269 SCV000893912 pathogenic Ceroid lipofuscinosis neuronal 2; Childhood-onset autosomal recessive slowly progressive spinocerebellar ataxia 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000792396 SCV000931692 pathogenic Neuronal ceroid lipofuscinosis 2019-04-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg127*) in the TPP1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs756564767, ExAC 0.01%). This variant has been observed in combination with another TPP1 variant in an individual affected with autosomal recessive neuronal ceroid lipofucinosis (PMID: 10330339). ClinVar contains an entry for this variant (Variation ID: 207569). Loss-of-function variants in TPP1 are known to be pathogenic (PMID: 10330339). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001004372 SCV001163322 pathogenic Ceroid lipofuscinosis neuronal 2 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV001004372 SCV001164345 pathogenic Ceroid lipofuscinosis neuronal 2 2018-12-03 criteria provided, single submitter research The homozygous p.Arg127Ter variant in TPP1 was identified by our study in one individual with Neuronal Ceroid Lipofuscinosis. The p.Arg127Ter variant in TPP has been reported in 8 individuals from Turkey, Mexico, US, German, UK, and Canada, with Neuronal Ceroid Lipofuscinosis, segregated with disease in 3 affected relatives from 1 families (PMID: 10330339, 21990111), and has been identified in 0.03196% (11/34420) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs756564767). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported pathogenic in ClinVar (Variation ID: 207569). This nonsense variant leads to a premature termination codon at position 127, which is predicted to lead to a truncated or absent protein. Loss of function of the TPP1 gene is an established disease mechanism in autosomal recessive Neuronal Ceroid Lipofuscinosis. The presence of this variant in combination with a reported pathogenic variant as well as a splice site variant absent from ClinVar, and in 3 individuals with Neuronal Ceroid Lipofuscinosis increases the likelihood that the p.Arg127Ter variant is pathogenic (PMID: 10330339, 21990111; Variation ID: 2643). In summary, this variant meets criteria to be classified as pathogenic for Neuronal Ceroid Lipofuscinosis in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with pathogenic TPP1 variants in individuals with Neuronal Ceroid Lipofuscinosis. ACMG/AMP Criteria applied: PM2, PVS1, PM3, PP1 (Richards 2015).
Integrated Genetics/Laboratory Corporation of America RCV000792396 SCV001361223 pathogenic Neuronal ceroid lipofuscinosis 2019-08-05 criteria provided, single submitter clinical testing Variant summary: TPP1 c.379C>T (p.Arg127X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 6.4e-05 in 251478 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TPP1 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (6.4e-05 vs 0.003), allowing no conclusion about variant significance. c.379C>T has been reported in the literature in at-least two individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease)(Sleat_1999, Scocchia_2019). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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