Submissions for variant NM_000391.4(TPP1):c.1525C>T (p.Gln509Ter)

gnomAD frequency: 0.00001  dbSNP: rs1184563885

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666347	SCV000790623	pathogenic	Neuronal ceroid lipofuscinosis 2	2017-03-30	criteria provided, single submitter	clinical testing
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000666347	SCV000891656	likely pathogenic	Neuronal ceroid lipofuscinosis 2	2017-12-30	criteria provided, single submitter	curation
Invitae	RCV001386654	SCV001586966	pathogenic	not provided	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln509*) in the TPP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 55 amino acid(s) of the TPP1 protein. This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with late-infantile neuronal ceroid lipofuscinosis (PMID: 10862088). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 551316). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526988	SCV001737786	pathogenic	Neuronal ceroid lipofuscinosis	2021-06-12	criteria provided, single submitter	clinical testing	Variant summary: TPP1 c.1525C>T (p.Gln509X) 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. One study reports that this results in a mutant allele that is translated into a shorter peptide, lacking the last 54 amino acids of the encoded protein (Tessa_2000). The variant allele was found at a frequency of 1.2e-05 in 251456 control chromosomes. c.1525C>T has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (example, Tessa_2000). 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. Three 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 (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002530680	SCV003761311	likely pathogenic	Autosomal recessive spinocerebellar ataxia 7	2023-01-25	criteria provided, single submitter	curation	The homozygous p.Gln509Ter variant in TPP1 was identified by our study in one individual with neurodegenerative disease with cerebellar atrophy. The p.Gln509Ter variant in TPP1 has been previously reported in 5 unrelated individuals with TPP1-related neurologic disease (PMID: 17690061, PMID: 10862088, PMID: 27217339) and segregated with disease in 7 affected relatives from three families (PMID: 17690061, PMID: 10862088), but has been identified in 0.003% (3/113742) of European (non-Finnish) chromosomes by Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1184563885). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 5 previously reported affected individuals (PMID: 17690061, PMID: 10862088, PMID: 27217339), 3 were homozygotes (PMID: 17690061, PMID: 10862088) and 2 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 10862088, ClinVar Variation ID: 2643; PMID: 27217339, ClinVar Variation ID: 2645), which increases the likelihood that the p.Gln509Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 551316) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 509. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the TPP1 gene is an established disease mechanism of autosomal recessive TPP1-related neurologic disease. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive TPP1-related neurologic disease. ACMG/AMP Criteria applied: PVS1_Moderate, PM2_Supporting, PM3_Strong, PP1_Moderate (Richards 2015).
Natera, Inc.	RCV000666347	SCV002094797	pathogenic	Neuronal ceroid lipofuscinosis 2	2021-10-14	no assertion criteria provided	clinical testing