ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.509-1G>A (rs56144125)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189764 SCV000243412 pathogenic not provided 2017-05-18 criteria provided, single submitter clinical testing c.509-1 G>A: IVS5-1 G>A in intron 5 of the TPP1 gene (NM_000391.3)The c.509-1 G>A splice site mutation mutation has been reported in multiple patients with late-infantile or juvenile neuronal ceroid lipofuscinosis who harbored a second mutation on the other chromosome (Sleat et al., 1999; Hartikainen et al., 1999). This mutation destroys the canonical splice acceptor site in intron 5 and is expected to cause abnormal gene splicing. Therefore, c.509-1 G>A is considered a disease-causing mutation in the TPP1 gene. The variant is found in INFANT-EPI,EPILEPSY panel(s).
Integrated Genetics/Laboratory Corporation of America RCV000586250 SCV000696665 pathogenic Neuronal ceroid lipofuscinosis 2016-02-18 criteria provided, single submitter clinical testing Variant summary: TPP1 c.509-1G>A is a splice-site variant that alters a conserved nucleotide. 5/5 in silico tools via Alamut predict this variant to disrupt a canonical acceptor sequence, which has been confirmed by Hartikainen et al (1999) who showed an aberrant splicing pattern. It has been reported in multiple affected individuals with LINCL with nearly absent residual enzyme activity (Perez-Poyato_JCN_2012 and Hartikainen_MGM_1999, respectively). The variant is present in ExAC at low frequency (0.0025%) which does not exceed the maximum frequency for a pathogenic variant in TPP1 gene (0.29%). Lastly, it has been classified as pathogenic via publications and/or reputable databases/clinical laboratories. Taken together, the variant was classified as Pathogenic.
Counsyl RCV000673911 SCV000799167 pathogenic Ceroid lipofuscinosis neuronal 2 2018-04-06 criteria provided, single submitter clinical testing
Invitae RCV000586250 SCV000949765 pathogenic Neuronal ceroid lipofuscinosis 2019-10-25 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the TPP1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs56144125, ExAC 0.005%). This variant has been observed in combination with other TPP1 variants in individuals affected with neuronal ceroid lipofuscinosis (PMID: 10330339, 10356316, 22832778). This variant is also referred to as c.3556G>A and T523-1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 207574). Experimental studies have shown that this splice site change causes aberrant mRNA splicing predicted to result in a premature stop codon and an absent protein product (PMID: 10356316). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TPP1 are known to be pathogenic (PMID: 10330339). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000189764 SCV000801148 pathogenic not provided 2015-10-22 no assertion criteria provided clinical testing

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