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

gnomAD frequency: 0.00004  dbSNP: rs756564767

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189759	SCV000243407	pathogenic	not provided	2022-03-15	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 26075876, 29631617, 28289221, 10330339, 21990111, 30792901, 31589614)
Fulgent Genetics, Fulgent Genetics	RCV000763269	SCV000893912	pathogenic	Neuronal ceroid lipofuscinosis 2; Autosomal recessive spinocerebellar ataxia 7	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000189759	SCV000931692	pathogenic	not provided	2024-01-10	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. Loss-of-function variants in TPP1 are known to be pathogenic (PMID: 10330339). This variant is present in population databases (rs756564767, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with autosomal recessive neuronal ceroid lipofucinosis (PMID: 10330339). ClinVar contains an entry for this variant (Variation ID: 207569). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001004372	SCV001163322	pathogenic	Neuronal ceroid lipofuscinosis 2		criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001004372	SCV001164345	pathogenic	Neuronal ceroid lipofuscinosis 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Revvity Omics, Revvity	RCV000189759	SCV002022405	pathogenic	not provided	2021-11-30	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV001804926	SCV002053839	pathogenic	Angelman syndrome		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001004372	SCV004801555	pathogenic	Neuronal ceroid lipofuscinosis 2	2018-05-02	criteria provided, single submitter	clinical testing	The TPP1 c.379C>T p.(Arg127Ter) variant is nonsense variant is expected to result in the loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been identified in individuals with a phenotype consistent with late infantile-onset NCL or undiagnosed lysosomal storage disorder (Sleat et al. 1999; Sleat et al. 2009; Di Fruscio et al. 2015). The highest frequency of this allele in the Genome Aggregation Database is 0.000032 in the Latino population (version 2.1.1). Functional studies of the variant have not been conducted, but deficient enzyme activity and protein expression were demonstrated in fibroblasts and post-mortem brain tissue from the compound heterozygous individuals. Based on the available evidence, the c.379C>T (p.(Arg127Ter) variant is classified as pathogenic for neuronal ceroid lipofuscinosis.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001004372	SCV005416587	pathogenic	Neuronal ceroid lipofuscinosis 2		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PM3_Strong+PP4
Natera, Inc.	RCV001004372	SCV002094874	pathogenic	Neuronal ceroid lipofuscinosis 2	2020-09-29	no assertion criteria provided	clinical testing