ClinVar Genomic variation as it relates to human health
NM_000391.4(TPP1):c.1016G>A (p.Arg339Gln)
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.
Pathogenic(1); Likely pathogenic(4); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000391.4(TPP1):c.1016G>A (p.Arg339Gln)
Variation ID: 198725 Accession: VCV000198725.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 6616374 (GRCh38) [ NCBI UCSC ] 11: 6637605 (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 Jun 29, 2015 Feb 14, 2024 Dec 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000391.4:c.1016G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000382.3:p.Arg339Gln missense NC_000011.10:g.6616374C>T NC_000011.9:g.6637605C>T NG_008653.1:g.8088G>A LRG_830:g.8088G>A LRG_830t1:c.1016G>A LRG_830p1:p.Arg339Gln O14773:p.Arg339Gln - Protein change
- R339Q
- Other names
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- Canonical SPDI
- NC_000011.10:6616373:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- variation affecting protein Variation Ontology [VariO:0002]
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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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
1150 | 1181 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Dec 13, 2023 | RCV000180153.15 | |
Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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May 18, 2021 | RCV000625040.6 |
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
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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
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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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Likely pathogenic
(Jul 28, 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:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000743598.1 First in ClinVar: Apr 20, 2018 Last updated: Apr 20, 2018 |
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Likely pathogenic
(Jun 17, 2016)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 2
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000744908.1 First in ClinVar: Apr 20, 2018 Last updated: Apr 20, 2018 |
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Uncertain significance
(Sep 17, 2014)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000232543.5
First in ClinVar: Jun 29, 2015 Last updated: Jun 29, 2015 |
Number of individuals with the variant: 2
Sex: mixed
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Likely pathogenic
(May 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 2
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001737219.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Sex: mixed
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Likely pathogenic
(Oct 15, 2020)
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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: SCV001778011.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This … (more)
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32298681, 30541466, 29056246, 23266810, 21990111, 19038966) (less)
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Pathogenic
(Dec 13, 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: SCV000827926.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 339 of the TPP1 protein (p.Arg339Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 339 of the TPP1 protein (p.Arg339Gln). This variant is present in population databases (rs765380155, gnomAD 0.0009%). This missense change has been observed in individual(s) with TPP1-related conditions (PMID: 22832778, 23266810). ClinVar contains an entry for this variant (Variation ID: 198725). 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%. This variant disrupts the p.Pro339 amino acid residue in TPP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24091540; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 29, 2021)
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no assertion criteria provided
Method: research
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Neuronal ceroid lipofuscinosis 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Human Genetics Research Lab, Central University of Jammu
Accession: SCV001762275.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
We confirmed the missense variation NC_00011.10:g.6616374C>T (NP_000382.3:p.Arg339Gln; rs765380155) in exon 8 of TPP1 gene, segregating with disease in family and in silico analyses predicted the … (more)
We confirmed the missense variation NC_00011.10:g.6616374C>T (NP_000382.3:p.Arg339Gln; rs765380155) in exon 8 of TPP1 gene, segregating with disease in family and in silico analyses predicted the variant to be highly pathogenic that corelated with pathologically low enzymatic activity of TPP1 in the proband's blood sample (<0.49 μmol/L/h; pathological reference = <0.5 μmol/L/h). Reference source OMIM: 204500 Neuronal ceroid lipofuscinosis-2 is caused by homozygous or compound heterozygous mutation in the TPP1 gene (607998) on chromosome 11p15. Reference source ClinVar: RCV000699225.1 NM_000391.4(TPP1):c.1016G>A (p.Arg339Gln) and Neuronal ceroid lipofuscinosis https://www.ncbi.nlm.nih.gov/clinvar/RCV000699225.1/ (less)
Age: 0-9 years
Sex: female
Ethnicity/Population group: Jammu and Kashmir Hindu
Geographic origin: India
Comment on evidence:
Variant segregating with disease in family in autosomal recessive manner where unaffected parents were found heterozygous whereas, affected patient was found Homozygous for the variation. … (more)
Variant segregating with disease in family in autosomal recessive manner where unaffected parents were found heterozygous whereas, affected patient was found Homozygous for the variation. The Patient also has shown pathologically low enzymatic activity of TPP1 in the blood sample (<0.49 μmol/L/h; pathological reference = <0.5 μmol/L/h). (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808621.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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variation affecting protein
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Human Genetics Research Lab, Central University of Jammu
Accession: SCV001762275.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Diagnostic utility of whole exome sequencing in patients showing cerebellar and/or vermis atrophy in childhood. | Ohba C | Neurogenetics | 2013 | PMID: 24091540 |
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 |
Late infantile neuronal ceroid lipofuscinosis: mutations in the CLN2 gene and clinical course in Spanish patients. | Pérez-Poyato MS | Journal of child neurology | 2013 | PMID: 22832778 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TPP1 | - | - | - | - |
Text-mined citations for rs765380155 ...
HelpRecord last updated Feb 20, 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.