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NM_000391.4(TPP1):c.1016G>A (p.Arg339Gln)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(4);Pathogenic(1);Uncertain significance(1)

Review status:
criteria provided, conflicting interpretations
Submissions:
8 (Most recent: Aug 24, 2021)
Last evaluated:
May 18, 2021
Accession:
VCV000198725.9
Variation ID:
198725
Description:
single nucleotide variant
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NM_000391.4(TPP1):c.1016G>A (p.Arg339Gln)

Allele ID
195886
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
11p15.4
Genomic location
11: 6616374 (GRCh38) GRCh38 UCSC
11: 6637605 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_830:g.8088G>A
LRG_830t1:c.1016G>A LRG_830p1:p.Arg339Gln
O14773:p.Arg339Gln
... more HGVS
Protein change
R339Q
Other names
-
Canonical SPDI
NC_000011.10:6616373:C:T
Functional consequence
variation affecting protein [Variation Ontology VariO:0002]
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Links
ClinGen: CA247530
UniProtKB: O14773#VAR_066886
dbSNP: rs765380155
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Likely pathogenic 4 criteria provided, multiple submitters, no conflicts May 18, 2021 RCV000625040.4
Conflicting interpretations of pathogenicity 4 criteria provided, conflicting interpretations Oct 15, 2020 RCV000180153.5
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
TPP1 - - GRCh38
GRCh37
623 645

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Sep 17, 2014)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics
Accession: SCV000232543.5
Submitted: (Sep 19, 2018)
Evidence details
Other databases
http://www.egl-eurofins.com/emvc…
Likely pathogenic
(May 18, 2021)
criteria provided, single submitter
Method: clinical testing
Ceroid lipofuscinosis neuronal 2
Allele origin: germline
Nilou-Genome Lab
Accession: SCV001737219.1
Submitted: (Jun 15, 2021)
Evidence details
Likely pathogenic
(Oct 15, 2020)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV001778011.1
Submitted: (Aug 10, 2021)
Evidence details
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)
Likely pathogenic
(Jul 28, 2017)
criteria provided, single submitter
Method: clinical testing
Ceroid lipofuscinosis neuronal 2
Allele origin: germline
Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000743598.1
Submitted: (Apr 17, 2018)
Evidence details
Likely pathogenic
(Jun 17, 2016)
criteria provided, single submitter
Method: clinical testing
Ceroid lipofuscinosis neuronal 2
Allele origin: germline
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000744908.1
Submitted: (Apr 09, 2018)
Evidence details
Pathogenic
(Jul 30, 2020)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Invitae
Accession: SCV000827926.3
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (4)
Comment:
This sequence change replaces arginine with glutamine at codon 339 of the TPP1 protein (p.Arg339Gln). The arginine residue is highly conserved and there is a … (more)
Pathogenic
(Jul 29, 2021)
no assertion criteria provided
Method: research
Ceroid lipofuscinosis neuronal 2
(Autosomal recessive inheritance)
Allele origin: germline
Human Genetics Research Group,Shri Mata Vaishno Devi University
Accession: SCV001762275.1
Submitted: (Aug 06, 2021)
Evidence details
Publications
DOI: 10.20944/preprints202107.06…
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)
Likely pathogenic
(-)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: germline
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808621.1
Submitted: (Aug 24, 2021)
Evidence details

Functional evidence

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Functional consequence Method Result Submitter Supporting information
variation affecting protein
  1. Method not provided
  1. Result not provided
Human Genetics Research Group,Shri Mata Vaishno Devi University
Accession: SCV001762275.1
Submitted: (Aug 06, 2021)
Evidence details
Publications
DOI: 10.20944/preprints202107.06…

Citations for this variant

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Title Author Journal Year Link
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
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 - - - -
- - - - DOI: 10.20944/preprints202107.0661.v1

Text-mined citations for rs765380155...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 27, 2021