Submissions for variant NM_000391.4(TPP1):c.184_185del (p.Ser62fs)

dbSNP: rs1554902216

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000667218	SCV000791636	likely pathogenic	Neuronal ceroid lipofuscinosis 2	2017-05-19	criteria provided, single submitter	clinical testing
Mendelics	RCV000988486	SCV001138228	pathogenic	Neuronal ceroid lipofuscinosis	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000988486	SCV003800752	likely pathogenic	Neuronal ceroid lipofuscinosis	2023-01-01	criteria provided, single submitter	clinical testing	Variant summary: TPP1 c.184_185delTC (p.Ser62GlyfsX25) 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. The variant was absent in 251362 control chromosomes. c.184_185delTC has been reported in the literature in at-least one individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (example, Lam_2001). 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003558491	SCV004295349	pathogenic	not provided	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser62Glyfs*25) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 11241479). This variant is also known as 1902delCT. ClinVar contains an entry for this variant (Variation ID: 552025). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.