ClinVar Miner

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

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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000189765 SCV000231528 pathogenic not provided 2017-04-26 criteria provided, single submitter clinical testing
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000002763 SCV000236538 pathogenic Ceroid lipofuscinosis neuronal 2 2014-01-13 criteria provided, single submitter clinical testing
GeneDx RCV000189765 SCV000243413 pathogenic not provided 2019-01-09 criteria provided, single submitter clinical testing The c.509-1 G>C variant in the TPP1 gene is a common pathogenic variant, sometimes reported using alternate nomenclature of T523-1 G>C or c.3556 G>C, that has been reported previously in both the homozygous and compound heterozygous state in association with infantile, late-infantile, and juvenile neuronal ceroid lipofuscinosis (Zhong et al., 1998; Sleat et al., 1999; Kousi et al., 2012). This pathogenic variant destroys the canonical splice acceptor site in intron 5, and is expected to cause abnormal gene splicing. The c.509-1 G>C variant, in trans with a pathogenic nonsense variant, resulted in a significant decrease in TPP1 enzyme activity in patient-derived lymphoblast cell lines (Miller et al., 2013). Therefore, the c.509-1 G>C variant is considered to be a pathogenic variant.
Ambry Genetics RCV000210689 SCV000262910 pathogenic Inborn genetic diseases 2017-09-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation ,Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous,Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes) ,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without splicing assay data in support of pathogenicity
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000002763 SCV000265553 pathogenic Ceroid lipofuscinosis neuronal 2 2015-02-10 criteria provided, single submitter research
Invitae RCV000228119 SCV000284807 pathogenic Neuronal ceroid lipofuscinosis 2018-12-26 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 0.06%). This variant has been reported in the homozygous or compound heterozygous state in individuals with late-infantile neuronal ceroid lipofuscinosis (PMID: 9295267, 9788728, 10330339, 12376936). This variant is also known as c.523-1G>C, c.3556G>C, and IVS5-1G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 2644). 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.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000189765 SCV000511402 pathogenic not provided 2017-02-16 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000002763 SCV000538068 pathogenic Ceroid lipofuscinosis neuronal 2 2015-10-23 criteria provided, single submitter clinical testing he c.509-1G>C variant is one of the most common pathogenic variants associated with LINCL and is found in both the homozygous or compound heterozygous state (Sleat DE et al., 1999; Zhong N et al., 1998; Kousi M et al., 2011). This variant was shown to segregate with disease in a non-consanguineous sib ship and in affected individuals who harbor this variant; enzyme activity in the leukocytes and fibroblasts was very low to almost absent respectively (Sun Y et al., 2013). Furthermore, the frequency of this variant is very low in the population database (1000 Genome, Exome Sequencing Project and ExAC). This locus is conserved across species and several computational algorithms predict the loss of splice-acceptor site in intron 5. Finally, several reputable clinical sources have classified this variant as pathogenic. In summary, the evidence meets our laboratory’s criteria for a Pathogenic classification
Genetic Services Laboratory, University of Chicago RCV000002763 SCV000597532 pathogenic Ceroid lipofuscinosis neuronal 2 2016-03-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000002763 SCV000611329 pathogenic Ceroid lipofuscinosis neuronal 2 2017-05-18 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000002763 SCV000680415 pathogenic Ceroid lipofuscinosis neuronal 2 2017-11-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000228119 SCV000696666 pathogenic Neuronal ceroid lipofuscinosis 2017-07-10 criteria provided, single submitter clinical testing Variant summary: The TPP1 c.509-1G>C variant (also known as G3556C) involves the alteration of a highly conserved nucleotide at canonical splice acceptor site in intron 5. 5/5 splice prediction tools predict abrogation of the splice-site. This variant was found in 43/121262 control chromosomes from ExAC at a frequency of 0.0003546, which does not exceed the estimated maximal expected allele frequency of a pathogenic TPP1 variant (0.002958). This variant is one of the most common pathogenic variants associated with LINCL and is found in both the homozygous and compound heterozygous state, including evidence of cosegregation with disease (Sleat_ 1999; Ju_2002; Worgall_2007). Enzyme activity in the in patients carrying this variant was very low to absent, suggesting it leads to loss of protein function (Sleat_1999). In addition, several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000002763 SCV000744910 pathogenic Ceroid lipofuscinosis neuronal 2 2015-09-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763268 SCV000893911 pathogenic Ceroid lipofuscinosis neuronal 2; Childhood-onset autosomal recessive slowly progressive spinocerebellar ataxia 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000002763 SCV000915544 pathogenic Ceroid lipofuscinosis neuronal 2 2018-08-14 criteria provided, single submitter clinical testing The TPP1 c.509-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.509-1G>C variant is described as one of the two most common pathogenic variants found in individuals with the classical late-infantile form of neuronal ceroid-lipofuscinosis (LINCL), often found in a compound heterozygous state with the other common variant, p.Arg508Ter. Together they account for up to 60% of pathogenic variants in the TPP1 gene (Zhong et al. 1998; Sleat et al. 1999; Steinfeld et al. 2002). Across a selection of the literature, the c.509-1G>C variant was detected in a total of 56 individuals affected with LINCL, including in ten individuals in a homozygous state, in 42 individuals in a compound heterozygous state (two of whom were related) and in four individuals in a heterozygous state in whom a second variant was not detected due to incomplete screening methods. The variant was also found in a heterozygous state in one unaffected family member (Sleat et al. 1997; Zhong et al. 1998; Sleat et al. 1999; Steinfeld et al. 2002). The variant was absent from 32 control chromosomes and is reported at a frequency of 0.001047 in the European American population of the Exome Sequencing Project. The variant results in a significant reduction in TPP1 protease activity to between 0 - 10% of wild type depending on the sample type (Sleat et al. 1999; Steinfeld et al. 2002; Miller et al. 2013). Based on the collective evidence and the potential impact of splice acceptor variants, the c.509-1G>C variant is classified as pathogenic for neuronal ceroid-lipofuscinosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM RCV000002763 SCV000022921 pathogenic Ceroid lipofuscinosis neuronal 2 2013-05-01 no assertion criteria provided literature only
GeneReviews RCV000002763 SCV000086784 pathologic Ceroid lipofuscinosis neuronal 2 2013-08-01 no assertion criteria provided curation Converted during submission to Pathogenic.
OMIM RCV000074608 SCV000108697 pathogenic Childhood-onset autosomal recessive slowly progressive spinocerebellar ataxia 2013-05-01 no assertion criteria provided literature only
Counsyl RCV000002763 SCV000485117 pathogenic Ceroid lipofuscinosis neuronal 2 2016-03-08 no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000002763 SCV000607111 not provided Ceroid lipofuscinosis neuronal 2 no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000002763 SCV000733090 pathogenic Ceroid lipofuscinosis neuronal 2 no assertion criteria provided clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000189765 SCV000801147 pathogenic not provided 2018-03-13 no assertion criteria provided clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000228119 SCV000804933 pathogenic Neuronal ceroid lipofuscinosis 2012-05-03 no assertion criteria provided clinical testing

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