ClinVar Miner

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

dbSNP: rs56144125
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189764 SCV000243412 pathogenic not provided 2024-06-15 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26143525, 22344438, 10356316, 10330339, 21940688, 31440721, 21990111)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 Neuronal ceroid lipofuscinosis 2 2018-04-06 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000189764 SCV000949765 pathogenic not provided 2024-01-24 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the TPP1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs56144125, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 10330339, 10356316, 22832778). This variant is also known as c.3556G>A and T523-1G>A. ClinVar contains an entry for this variant (Variation ID: 207574). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 10356316). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002336504 SCV002642960 pathogenic Inborn genetic diseases 2018-06-20 criteria provided, single submitter clinical testing The c.509-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 6 of the TPP1 gene. This mutation (reported as T523-1G>A or 3556G>A) has been reported in multiple unrelated individuals with late-infantile neuronal ceroid lipofuscinosis (NCL) who carried a second mutation (Hartikainen JM et al. Mol. Genet. Metab., 1999 Jun;67:162-8; Sleat DE et al. Am. J. Hum. Genet., 1999 Jun;64:1511-23). In addition, analysis of mRNA from one patient revealed that this mutation resulted in an insertion of the adjacent intronic sequence (Hartikainen JM et al. Mol. Genet. Metab., 1999 Jun;67:162-8). A different alteration at the same position (c.509-1G>C), resulting in the same aberrant splicing, is also one of the most common mutations associated with NCL. In addition to these data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Mayo Clinic Laboratories, Mayo Clinic RCV000189764 SCV000801148 pathogenic not provided 2015-10-22 no assertion criteria provided clinical testing
Natera, Inc. RCV000673911 SCV002094869 pathogenic Neuronal ceroid lipofuscinosis 2 2021-07-21 no assertion criteria provided clinical testing

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