11-6617040-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000391.4(TPP1):c.622C>T(p.Arg208Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000306 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00031 ( 0 hom. )
Consequence
TPP1
NM_000391.4 stop_gained
NM_000391.4 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 3.17
Genes affected
TPP1 (HGNC:2073): (tripeptidyl peptidase 1) This gene encodes a member of the sedolisin family of serine proteases. The protease functions in the lysosome to cleave N-terminal tripeptides from substrates, and has weaker endopeptidase activity. It is synthesized as a catalytically-inactive enzyme which is activated and auto-proteolyzed upon acidification. Mutations in this gene result in late-infantile neuronal ceroid lipofuscinosis, which is associated with the failure to degrade specific neuropeptides and a subunit of ATP synthase in the lysosome. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-6617040-G-A is Pathogenic according to our data. Variant chr11-6617040-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6617040-G-A is described in Lovd as [Pathogenic]. Variant chr11-6617040-G-A is described in Lovd as [Pathogenic]. Variant chr11-6617040-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TPP1 | NM_000391.4 | c.622C>T | p.Arg208Ter | stop_gained | 6/13 | ENST00000299427.12 | NP_000382.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TPP1 | ENST00000299427.12 | c.622C>T | p.Arg208Ter | stop_gained | 6/13 | 1 | NM_000391.4 | ENSP00000299427 | P1 |
Frequencies
GnomAD3 genomes 0.000256 AC: 39AN: 152116Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000223 AC: 56AN: 251232Hom.: 0 AF XY: 0.000199 AC XY: 27AN XY: 135798
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GnomAD4 exome AF: 0.000311 AC: 455AN: 1461860Hom.: 0 Cov.: 42 AF XY: 0.000329 AC XY: 239AN XY: 727236
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GnomAD4 genome 0.000256 AC: 39AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74314
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:29Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neuronal ceroid lipofuscinosis 2 Pathogenic:13Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Sep 25, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 22, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Nov 02, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 14, 2018 | 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. - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 19, 1997 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 09, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jan 18, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Nov 07, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 18, 2019 | 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 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
not provided Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 16, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 18, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 22, 2021 | 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) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 24, 2023 | PM2, PS3, PS4_moderate, PVS1 - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | TPP1: PM3:Very Strong, PVS1, PM2, PS3:Supporting - |
Autosomal recessive spinocerebellar ataxia 7;C1876161:Neuronal ceroid lipofuscinosis 2 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 31, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Neuronal ceroid lipofuscinosis Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Aug 17, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 11, 2016 | 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. - |
TPP1-related disorder Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 23, 2024 | The TPP1 c.622C>T variant is predicted to result in premature protein termination (p.Arg208*). This is one of the most commonly reported TPP1 variants in individuals with neuronal ceroid lipofuscinosis; it has been observed in the homozygous state or with a second TPP1 variant in affected individuals (for example, see Sleat et al. 1997. PubMed ID: 9295267; Barisić et al. 2003. PubMed ID: 12950156; Miller et al. 2013. PubMed ID: 23539563; Geraets et al. 2017. PubMed ID: 28464005). This variant is reported in 0.048% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Nonsense variants in TPP1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Mar 11, 2024 | PVS1, PM3_Strong - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 26, 2021 | The c.622C>T (p.R208*) alteration, located in exon 6 (coding exon 6) of the TPP1 gene, consists of a C to T substitution at nucleotide position 622. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 208. 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. 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 (Sleat, 1997; Barisi, 2003; Miller, 2013; Helbig, 2016). This mutation has been shown to significantly impact both TPP1 fold regulation and enzyme activity (Miller, 2013). Based on the available evidence, this alteration is classified as pathogenic. - |
Abnormality of the nervous system Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Computational scores
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Name
Calibrated prediction
Score
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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Details are displayed if max score is > 0.2
DS_DG_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at