ClinVar Miner

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

gnomAD frequency: 0.00038  dbSNP: rs56144125
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Total submissions: 34
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD LLC (GA) RCV000189765 SCV000231528 pathogenic not provided 2017-04-26 criteria provided, single submitter clinical testing
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000002763 SCV000236538 pathogenic Neuronal ceroid lipofuscinosis 2 2014-01-13 criteria provided, single submitter clinical testing
GeneDx RCV000189765 SCV000243413 pathogenic not provided 2022-01-28 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Different variant affecting the same splice site (c.509-1G>A) has been reported as pathogenic in the Human Gene Mutation Database and at GeneDx in association with NCL (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 26026925, 26143525, 25976102, 26795593, 28335910, 10330339, 9788728, 26224725, 28554332, 9295267, 29056246, 29631617, 29655203, 30283815, 30548430, 31487502, 32631363, 31980526, 33845243, 12376936, 32298681, 31589614, 21990111, 23539563, 35054396, 34831035)
Ambry Genetics RCV000210689 SCV000262910 pathogenic Inborn genetic diseases 2018-08-23 criteria provided, single submitter clinical testing The c.509-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 6 of the TPP1 gene. This mutation has been well described as one of the most common mutations causing late infantile neuronal ceroid lipofuscinosis (CLN2), having been reported in the homozygous and compound heterozygous state in numerous affected individuals across various ethnic backgrounds (Williams RE et al. Pediatr. Neurol., 2017 Apr;69:102-112; Sleat DE et al. Am. J. Hum. Genet. 1999;64(6):1511-23, Zhong N et al. Clin. Genet. 1998;54(3):234-8). This mutation has also been reported in individuals with autosomal recessive spinocereballar ataxia (SCAR7) (Dy ME, et al. Neurology 2015;85(14):1259-61). In one RNA study, RT-PCR analysis revealed retention of intron 5, resulting in a frameshift and premature protein truncation. Furthermore, residual enzyme activity in probands was reduced to 9% in CLN2 and 15% in SCAR7 compared to unaffected family members (Miller JN et al. Hum. Mol. Genet. 2013;22(13):2723-34). Based on the available evidence, c.509-1G>C is classified as a pathogenic mutation.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000002763 SCV000265553 pathogenic Neuronal ceroid lipofuscinosis 2 2015-02-10 criteria provided, single submitter research
Invitae RCV000189765 SCV000284807 pathogenic not provided 2020-10-31 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 Neuronal ceroid lipofuscinosis 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 Neuronal ceroid lipofuscinosis 2 2016-03-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000002763 SCV000611329 pathogenic Neuronal ceroid lipofuscinosis 2 2017-05-18 criteria provided, single submitter clinical testing
Institute of Human Genetics, Klinikum rechts der Isar RCV000002763 SCV000680415 pathogenic Neuronal ceroid lipofuscinosis 2 2017-11-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000002763 SCV000744910 pathogenic Neuronal ceroid lipofuscinosis 2 2015-09-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763268 SCV000893911 pathogenic Neuronal ceroid lipofuscinosis 2; Autosomal recessive spinocerebellar ataxia 7 2018-10-31 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000002763 SCV000915544 pathogenic Neuronal ceroid lipofuscinosis 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.
Baylor Genetics RCV000002763 SCV001163321 pathogenic Neuronal ceroid lipofuscinosis 2 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000002763 SCV001194046 pathogenic Neuronal ceroid lipofuscinosis 2 2019-11-18 criteria provided, single submitter clinical testing NM_000391.3(TPP1):c.509-1G>C(aka IVS5-1G>C) is classified as pathogenic in the context of TPP1-related neuronal ceroid lipofuscinosis and is associated with the late-infantile form of the disease. Sources cited for classification include the following: PMID 9788728, 11339651 and 18684116. Classification of NM_000391.3(TPP1):c.509-1G>C(aka IVS5-1G>C) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã
CeGaT Center for Human Genetics Tuebingen RCV000189765 SCV001249322 pathogenic not provided 2022-05-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000002763 SCV001366363 pathogenic Neuronal ceroid lipofuscinosis 2 2019-04-05 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PP3.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000002763 SCV002009210 pathogenic Neuronal ceroid lipofuscinosis 2 2021-11-03 criteria provided, single submitter clinical testing
New York Genome Center RCV000002763 SCV002097939 pathogenic Neuronal ceroid lipofuscinosis 2 2021-02-22 criteria provided, single submitter clinical testing
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000002763 SCV002587053 pathogenic Neuronal ceroid lipofuscinosis 2 2021-07-13 criteria provided, single submitter research
OMIM RCV000002763 SCV000022921 pathogenic Neuronal ceroid lipofuscinosis 2 2013-05-01 no assertion criteria provided literature only
GeneReviews RCV000002763 SCV000086784 pathologic Neuronal ceroid lipofuscinosis 2 2013-08-01 no assertion criteria provided curation Converted during submission to Pathogenic.
OMIM RCV000074608 SCV000108697 pathogenic Autosomal recessive spinocerebellar ataxia 7 2013-05-01 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000763268 SCV000607111 not provided Neuronal ceroid lipofuscinosis 2; Autosomal recessive spinocerebellar ataxia 7 no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 07/28/2014 by Lab or GTR ID 1006. 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 Neuronal ceroid lipofuscinosis 2 no assertion criteria provided clinical testing
Mayo Clinic 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
Natera, Inc. RCV000002763 SCV001459950 pathogenic Neuronal ceroid lipofuscinosis 2 2020-09-16 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000189765 SCV001797464 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000189765 SCV001807991 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000189765 SCV001926884 pathogenic not provided no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000189765 SCV002022408 pathogenic not provided 2021-07-14 no assertion criteria provided clinical testing

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