ClinVar Genomic variation as it relates to human health
NM_000391.4(TPP1):c.1424C>T (p.Ser475Leu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000391.4(TPP1):c.1424C>T (p.Ser475Leu)
Variation ID: 68741 Accession: VCV000068741.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 6615172 (GRCh38) [ NCBI UCSC ] 11: 6636403 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 31, 2013 Feb 14, 2024 Aug 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000391.4:c.1424C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000382.3:p.Ser475Leu missense NC_000011.10:g.6615172G>A NC_000011.9:g.6636403G>A NG_008653.1:g.9290C>T LRG_830:g.9290C>T LRG_830t1:c.1424C>T LRG_830p1:p.Ser475Leu O14773:p.Ser475Leu - Protein change
- S475L
- Other names
- 5541C>T
- Canonical SPDI
- NC_000011.10:6615171:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00040 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TPP1 | - | - |
GRCh38 GRCh37 |
1151 | 1182 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Apr 13, 2023 | RCV000059623.3 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 18, 2023 | RCV000800616.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 7, 2022 | RCV002307388.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Oct 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002600335.1
First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022 |
Comment:
Variant summary: TPP1 c.1424C>T (p.Ser475Leu) results in a non-conservative amino acid change located in the Peptidase S8/S53 domain (IPR000209) of the encoded protein sequence. Five … (more)
Variant summary: TPP1 c.1424C>T (p.Ser475Leu) results in a non-conservative amino acid change located in the Peptidase S8/S53 domain (IPR000209) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. The variant allele was found at a frequency of 2.4e-05 in 251484 control chromosomes (gnomAD). c.1424C>T has been reported in the literature as a biallelic genotype in individuals affected with Neuronal Ceroid-Lipofuscinosis (e.g. Sleat_1999, Dozieres-Puyravel_2020) and refractory epilepsy with intellectual disability (e.g. Long_2019). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating the variant in Chinese Hamster Ovary cells showed that the variant had no detectable enzymatic activity (0% of wild-type) despite normal translation, post translational processing, and trafficking (Walus_2010). Five ClinVar submitters have assessed the variant since 2014: two classified the variant as likely pathogenic, and three as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Sep 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002020274.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Aug 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000940342.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPP1 function (PMID: 20340139). An algorithm … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPP1 function (PMID: 20340139). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 68741). This missense change has been observed in individual(s) with TPP1-related conditions (PMID: 10330339, 21990111, 23266810). This variant is present in population databases (rs121908202, gnomAD 0.01%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 475 of the TPP1 protein (p.Ser475Leu). (less)
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Likely pathogenic
(Mar 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 2
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000790555.1
First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013 |
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Pathogenic
(Dec 17, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001818976.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Published functional studies demonstrate that the S475L variant results in no measurable TPP1 activity compared to wild type (Walus et al., 2010); In silico analysis, … (more)
Published functional studies demonstrate that the S475L variant results in no measurable TPP1 activity compared to wild type (Walus et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 31216804, 31283065, 31059981, 31139143, 25976102, 19246452, 15965709, 10477428, 11054422, 10330339, 19038966, 20340139, 21990111, 23266810) (less)
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Pathogenic
(Apr 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV003915842.1
First in ClinVar: Apr 23, 2023 Last updated: Apr 23, 2023 |
Comment:
A Homozygous missense variation in exon 11 of the TPP1 gene that results in the amino acid substitution of Leucine for Serine at codon 475 … (more)
A Homozygous missense variation in exon 11 of the TPP1 gene that results in the amino acid substitution of Leucine for Serine at codon 475 was detected. The observed variant c.1424C>T (p.Ser475Leu) has not been reported in the 1000 genomes and has a MAF of 0.0024% in the gnomAD databases. The in silico prediction of the variant are possibly damaging by PolyPhen-2, SIFT, FATHMM and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. (less)
Clinical Features:
Myoclonus (present) , Intellectual disability (present) , Profound global developmental delay (present)
Age: 0-9 years
Sex: male
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Neuronal ceroid lipofuscinosis 2
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001455826.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: not provided
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Ceroid lipofuscinosis, neuronal, 2
Affected status: not provided
Allele origin:
not provided
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UniProtKB/Swiss-Prot
Accession: SCV000091190.1
First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Paediatric-onset neuronal ceroid lipofuscinosis: first symptoms and presentation at diagnosis. | Dozières-Puyravel B | Developmental medicine and child neurology | 2020 | PMID: 31489614 |
The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children. | Long S | Frontiers in neurology | 2019 | PMID: 31139143 |
Neuronal ceroid lipofuscinosis type CLN2: a new rationale for the construction of phenotypic subgroups based on a survey of 25 cases in South America. | Kohan R | Gene | 2013 | PMID: 23266810 |
Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. | Kousi M | Human mutation | 2012 | PMID: 21990111 |
Functional consequences and rescue potential of pathogenic missense mutations in tripeptidyl peptidase I. | Walus M | Human mutation | 2010 | PMID: 20340139 |
Structure of tripeptidyl-peptidase I provides insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis. | Pal A | The Journal of biological chemistry | 2009 | PMID: 19038966 |
The human CLN2 protein/tripeptidyl-peptidase I is a serine protease that autoactivates at acidic pH. | Lin L | The Journal of biological chemistry | 2001 | PMID: 11054422 |
Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder. | Sleat DE | American journal of human genetics | 1999 | PMID: 10330339 |
Text-mined citations for rs121908202 ...
HelpRecord last updated Mar 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.