Submissions for variant NM_000391.4(TPP1):c.274del (p.Ser92fs)

gnomAD frequency: 0.00001  dbSNP: rs1064793806

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480719	SCV000567079	pathogenic	not provided	2015-07-07	criteria provided, single submitter	clinical testing	The c.274delT deletion in the TPP1 gene has been reported previously, using alternative nomenclature ofdelT2979, in an individual with neuronal ceroid lipfuscinosis who harbored a second TPP1 variant on theother allele and whose enzyme studies showed a loss of TPP1 enzyme activity (Sleath et al., 2009). Thedeletion causes a frameshift starting with codon Serine 92, changes this amino acid to a Proline residue andcreates a premature Stop codon at position 3 of the new reading frame, denoted p.Ser92ProfsX3. Thisdeletion is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, based on currently available information, c.274delT is interpreted to bea pathogenic variant.
Invitae	RCV000480719	SCV004295348	pathogenic	not provided	2023-02-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser92Profs*3) 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 lysosomal storage disorder (PMID: 19383612). This variant is also known as delT2979 . ClinVar contains an entry for this variant (Variation ID: 419346). For these reasons, this variant has been classified as Pathogenic.