Submissions for variant NM_000310.4(PPT1):c.362+5G>A

dbSNP: rs796052924

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188713	SCV000242337	pathogenic	not provided	2013-07-19	criteria provided, single submitter	clinical testing	c.362+5 G>A: IVS3+5 G>A in intron 3 of the PPT1 gene (NM_000310.3). The c.362+5 G>A is predicted to destroy the consensus splice donor site in intron 3, leading to abnormal gene splicing. Although this mutation has not been previously reported to our knowledge, other mutations affecting this splice donor site have been reported in association with neuronal ceroid lipofuscinosis (NCL). Therefore, c.362+5 G>A is considered a disease-causing mutation. The variant is found in EPILEPSY panel(s).
Invitae	RCV001090090	SCV003450384	uncertain significance	Neuronal ceroid lipofuscinosis 1	2022-03-29	criteria provided, single submitter	clinical testing	This sequence change falls in intron 3 of the PPT1 gene. It does not directly change the encoded amino acid sequence of the PPT1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with neurodevelopmental conditions, leukodystrophy, and epilepsy and/or PPT-related conditions (PMID: 29655203, 33547378; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 206643). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
3billion	RCV001090090	SCV004013803	uncertain significance	Neuronal ceroid lipofuscinosis 1		criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Intron variant. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.91). The variant has been reported to be associated with PPT1 related disorder (ClinVar ID: VCV000206643 / PMID: 29655203). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as Uncertain significance according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV001090090	SCV004204150	likely pathogenic	Neuronal ceroid lipofuscinosis 1	2023-07-06	criteria provided, single submitter	clinical testing
Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence,	RCV001090090	SCV001244931	uncertain significance	Neuronal ceroid lipofuscinosis 1		no assertion criteria provided	clinical testing