Submissions for variant NM_000391.4(TPP1):c.1496dup (p.Leu500fs)

dbSNP: rs756963463

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001551129	SCV001771567	likely pathogenic	not provided	2020-05-18	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 64 amino acids are replaced with 17 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 30792901)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001551129	SCV002217829	pathogenic	not provided	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu500Serfs*18) in the TPP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 64 amino acid(s) of the TPP1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with TPP1-related conditions (PMID: 30792901). ClinVar contains an entry for this variant (Variation ID: 1190419). This variant disrupts a region of the TPP1 protein in which other variant(s) (p.Trp542*) have been determined to be pathogenic (PMID: 31283065; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV003985101	SCV004801556	pathogenic	Neuronal ceroid lipofuscinosis 2	2022-07-19	criteria provided, single submitter	clinical testing	The TPP1 c.1496dupC p.(Leu500SerfsTer18) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. To our knowledge, this variant has not been reported in the peer-reviewed literature. This variant is not observed in version 2.1.1 of the Genome Aggregation Database. Based on the available evidence, the c.1496dupC p.(Leu500SerfsTer18) variant is classified as pathogenic for neuronal ceroid lipofuscinosis.