ClinVar Genomic variation as it relates to human health
NM_000391.4(TPP1):c.1340G>A (p.Arg447His)
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.1340G>A (p.Arg447His)
Variation ID: 2645 Accession: VCV000002645.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 6615256 (GRCh38) [ NCBI UCSC ] 11: 6636487 (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 Apr 15, 2024 Apr 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000391.4:c.1340G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000382.3:p.Arg447His missense NC_000011.10:g.6615256C>T NC_000011.9:g.6636487C>T NG_008653.1:g.9206G>A LRG_830:g.9206G>A LRG_830t1:c.1340G>A LRG_830p1:p.Arg447His O14773:p.Arg447His - Protein change
- R447H
- Other names
- 5457G>A
- p.R447H:CGT>CAT
- Canonical SPDI
- NC_000011.10:6615255:C:T
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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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
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
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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 |
1152 | 1183 |
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
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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 (6) |
criteria provided, multiple submitters, no conflicts
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Apr 4, 2024 | RCV000002764.12 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 20, 2023 | RCV000189790.6 |
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
(Dec 18, 2017)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 2
Affected status: yes
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000746792.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 11, 2022 |
Age: 0-9 years
Sex: male
Geographic origin: Iran
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Likely pathogenic
(Apr 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 2
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809407.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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Pathogenic
(Aug 18, 2015)
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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: SCV000243438.14
First in ClinVar: Aug 07, 2015 Last updated: May 29, 2016 |
Comment:
p.Arg447His (CGT>CAT): c.1340 G>A in exon 11 of the TPP1 gene (NM_000391.3)The Arg447His missense mutation has been observed in multiple patients with neuronal ceroid-lipofuscuinosis 2 … (more)
p.Arg447His (CGT>CAT): c.1340 G>A in exon 11 of the TPP1 gene (NM_000391.3)The Arg447His missense mutation has been observed in multiple patients with neuronal ceroid-lipofuscuinosis 2 (CLN2) who harbored a second disease causing mutation on the other chromosome (Sleat et al., 1999). Although this mutation is a conservative substitution of one positively charged polar amino acid for another, it alters a conserved region of the TPP1 protein and other mutations at nearby codons have been reported in association with CLN2. In addition, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, the Arg477His is considered a disease-causing mutation in the TPP1 gene. The variant is found in EPILEPSY panel(s). (less)
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Pathogenic
(Nov 20, 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: SCV001217719.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 447 of the TPP1 protein (p.Arg447His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 447 of the TPP1 protein (p.Arg447His). This variant is present in population databases (rs119455956, gnomAD 0.002%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 10330339, 20340139). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2645). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TPP1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TPP1 function (PMID: 20340139). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 01, 1999)
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no assertion criteria provided
Method: literature only
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CEROID LIPOFUSCINOSIS, NEURONAL, 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022922.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 20, 2015 |
Comment on evidence:
In 2 unrelated patients with juvenile-onset neuronal ceroid lipofuscinosis-2 (CLN2; 204500), Sleat et al. (1999) identified a rare monoallelic mutation that resulted in an arg447-to-his … (more)
In 2 unrelated patients with juvenile-onset neuronal ceroid lipofuscinosis-2 (CLN2; 204500), Sleat et al. (1999) identified a rare monoallelic mutation that resulted in an arg447-to-his (R447H) substitution in the CLN2 gene. Both of these patients were compound heterozygous, with either a monoallelic common splice junction mutation (607998.0004) or the arg208-to-ter mutation (R208X; 607998.0003). Both patients were originally diagnosed with juvenile-onset CLN3 (204200) on the basis of age at onset, age at death, and inclusion morphology. Sleat et al. (1999) considered it likely that the R447H mutation caused incomplete loss of function of the CLN2 protease, resulting in the protracted phenotype. The findings indicated that an attenuated form of CLN2 (i.e., with juvenile onset) may not be correctly diagnosed or may be confused with other later-onset neurodegenerative disorders. Such observations are not uncommon with other lysosomal storage diseases, in which missense mutations result in a partial dysfunction and subsequent mild or protracted phenotype. The possible phenotype of an individual homozygous for the R447H allele remained unknown. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: case-control
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Ceroid lipofuscinosis, neuronal, 2
Affected status: unknown
Allele origin:
biparental
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Medical Genetic Institute of Henan Province, Henan Provincial People’s Hospital
Accession: SCV002060995.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
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Pathogenic
(Jan 25, 2021)
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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: SCV002094812.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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: SCV000091187.1
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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Functional consequences and rescue potential of pathogenic missense mutations in tripeptidyl peptidase I. | Walus M | Human mutation | 2010 | PMID: 20340139 |
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 rs119455956 ...
HelpRecord last updated Jun 23, 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.