ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.622C>T (p.Arg208Ter)

gnomAD frequency: 0.00025  dbSNP: rs119455955
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Total submissions: 25
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189769 SCV000243417 pathogenic not provided 2021-04-22 criteria provided, single submitter clinical testing Published functional studies demonstrate damaging effects, including a reduction in transcript abundance and enzyme activity (Geraets et al., 2017); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19793312, 23539563, 12363103, 9788728, 21940688, 11071145, 12414822, 12796825, 18283468, 26795593, 29631617, 29554876, 15317752, 25525159, 20301601, 10665500, 18684116, 21990111, 9295267, 10330339, 12950156, 28464005, 29655203, 30541466, 30945278, 31170314, 31122803, 31980526, 32412666, 33845243, 31589614)
Ambry Genetics RCV000210605 SCV000262903 pathogenic Inborn genetic diseases 2016-11-30 criteria provided, single submitter clinical testing The p.R208* pathogenic mutation (also known as c.622C>T), located in coding exon 6 of the TPP1 gene, results from a C to T substitution at nucleotide position 622. This changes the amino acid from an arginine to a stop codon within coding exon 6. This mutation is one of the most common TPP1 mutations and has been detected in both the homozygous and compound heterozygous states in various individuals with neuronal ceroid lipofuscinosis (NCL) (Sleat DE et al. Science, 1997 Sep;277:1802-5; Barisić N et al. Croat. Med. J., 2003 Aug;44:489-93; Helbig KL et al. Genet. Med., 2016 Sep;18:898-905; Miller JN et al. Hum. Mol. Genet., 2013 Jul;22:2723-34). In addition, this mutation has been shown to significantly impact both TPP1 fold regulation and enzyme activity (Miller JN et al. Hum. Mol. Genet., 2013 Jul;22:2723-34). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000189769 SCV000284808 pathogenic not provided 2021-12-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg208*) in the TPP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TPP1 are known to be pathogenic (PMID: 10330339). This variant is present in population databases (rs119455955, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9295267, 10330339, 23539563, 26026925, 26795593). ClinVar contains an entry for this variant (Variation ID: 2643). For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory,University of Chicago RCV000002762 SCV000597531 pathogenic Neuronal ceroid lipofuscinosis 2 2016-03-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000002762 SCV000611330 pathogenic Neuronal ceroid lipofuscinosis 2 2017-05-18 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000189769 SCV000615830 pathogenic not provided 2017-02-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000230952 SCV000696667 pathogenic Neuronal ceroid lipofuscinosis 2016-08-11 criteria provided, single submitter clinical testing Variant summary: The TPP1 c.622C>T (p.Arg208X) variant results in a premature termination codon, predicted to cause a truncated or absent TPP1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 21/121276 control chromosomes at a frequency of 0.0001732, which does not exceed the estimated maximal expected allele frequency of a pathogenic TPP1 variant (0.002958). The variant has been reported in numerous affected individuals in the literature in the homozygous and compound heterozygous state and is reported as one of the most common pathogenic variants in the gene. In vitro functional studies reveal no translational product could be detected for the R208X mutant and enzyme activity was shown to be <10% and not significantly different from negative controls (Steinfeld_2004). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is a common disease causing variant and has been classified as pathogenic.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000002762 SCV000744909 pathogenic Neuronal ceroid lipofuscinosis 2 2017-11-07 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763267 SCV000893910 pathogenic Neuronal ceroid lipofuscinosis 2; Autosomal recessive spinocerebellar ataxia 7 2018-10-31 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000002762 SCV000915543 pathogenic Neuronal ceroid lipofuscinosis 2 2018-08-14 criteria provided, single submitter clinical testing The TPP1 c.622C>T (p.Arg208Ter) variant is a stop-gained variant predicted to result in in a premature termination of the protein. The p.Arg206Ter variant has been reported in at least five studies in which it was identified in 31 affected individuals, including in six in a homozygous state and in 25 in a compound heterozygous state, two of whom are siblings (Sleat et al. 1997; Sleat et al. 1999; Barisić et al. 2003; Helbig et al. 2016). Thirty of the individuals were diagnosed with neuronal ceroid-lipofuscinoses with one compound heterozygote presenting with a diagnosis of focal epilepsy (Helbig et al. 2016). In one study, the p.Arg208Ter variant accounted for 28% of disease alleles. The variant was absent from four controls but is reported at a frequency of 0.000619 in the Other population of the Genome Aggregation Database. Functional studies in HEK and CHO cells transfected with the variant showed that the variant resulted in enzymatic activity of 3.3% and 2.8% respectively compared to 100% in wild type (Steinfeld et al. 2004). A mouse model created by Geraets et al. (2017) mimicked the human disease very closely. TPP1 activity was found to be reduced by at least 90% compared to the wild type mice with Cln2 transcript levels reduced by 60-90% in tissue samples from a range of organs. Based on the collective evidence, the p.Arg208Ter 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 RCV000002762 SCV001163320 pathogenic Neuronal ceroid lipofuscinosis 2 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000002762 SCV001194158 pathogenic Neuronal ceroid lipofuscinosis 2 2019-10-18 criteria provided, single submitter clinical testing NM_000391.3(TPP1):c.622C>T(R208*) is classified as pathogenic in the context of TPP1-related neuronal ceroid lipofuscinosis and is associated with the late-infantile form of this disease. Sources cited for classification include the following: PMID 15317752, 9788728, 21990111, 23539563 and 10330339. Classification of NM_000391.3(TPP1):c.622C>T(R208*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000002762 SCV001366393 pathogenic Neuronal ceroid lipofuscinosis 2 2019-01-09 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Blueprint Genetics RCV000002762 SCV001426166 pathogenic Neuronal ceroid lipofuscinosis 2 2018-09-25 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000189769 SCV001748276 pathogenic not provided 2021-07-01 criteria provided, single submitter clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center RCV001813939 SCV001755651 pathogenic Abnormality of the nervous system 2021-07-10 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000002762 SCV002580602 pathogenic Neuronal ceroid lipofuscinosis 2 2022-01-18 criteria provided, single submitter clinical testing
OMIM RCV000002762 SCV000022920 pathogenic Neuronal ceroid lipofuscinosis 2 1997-09-19 no assertion criteria provided literature only
GeneReviews RCV000002762 SCV000086785 not provided Neuronal ceroid lipofuscinosis 2 no assertion provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000002762 SCV000733089 pathogenic Neuronal ceroid lipofuscinosis 2 no assertion criteria provided clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000230952 SCV000804935 pathogenic Neuronal ceroid lipofuscinosis 2012-08-17 no assertion criteria provided clinical testing
Natera, Inc. RCV000002762 SCV001459947 pathogenic Neuronal ceroid lipofuscinosis 2 2020-09-16 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000189769 SCV001798173 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000189769 SCV001959365 pathogenic not provided no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000189769 SCV002022403 pathogenic not provided 2021-04-07 no assertion criteria provided clinical testing

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