ClinVar Genomic variation as it relates to human health
NM_001032283.3(TMPO):c.565+1696C>T
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.
Uncertain significance(1); Benign(1); Likely benign(9)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001032283.3(TMPO):c.565+1696C>T
Variation ID: 192133 Accession: VCV000192133.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q23.1 12: 98533534 (GRCh38) [ NCBI UCSC ] 12: 98927312 (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 8, 2015 Mar 16, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001032283.3:c.565+1696C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001032284.3:c.565+1696C>T intron variant NM_001307975.2:c.565+1696C>T intron variant NM_003276.2:c.1277C>T NP_003267.1:p.Pro426Leu missense NC_000012.12:g.98533534C>T NC_000012.11:g.98927312C>T NG_021393.1:g.22962C>T LRG_443:g.22962C>T LRG_443t2:c.1277C>T LRG_443p2:p.Pro426Leu - Protein change
- P426L
- Other names
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- Canonical SPDI
- NC_000012.12:98533533: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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00108
Trans-Omics for Precision Medicine (TOPMed) 0.00117
The Genome Aggregation Database (gnomAD), exomes 0.00125
Exome Aggregation Consortium (ExAC) 0.00142
The Genome Aggregation Database (gnomAD) 0.00142
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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TMPO | - | - |
GRCh38 GRCh37 |
539 | 653 |
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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Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Feb 15, 2022 | RCV000172597.18 | |
Likely benign (2) |
criteria provided, single submitter
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Feb 12, 2022 | RCV000223911.16 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 1, 2017 | RCV000578085.9 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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May 26, 2016 | RCV000625188.10 | |
Benign (1) |
criteria provided, single submitter
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Jul 13, 2018 | RCV000852682.9 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV001081032.15 | |
Likely benign (1) |
criteria provided, single submitter
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Nov 12, 2018 | RCV002312700.8 | |
Likely benign (1) |
criteria provided, single submitter
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Feb 3, 2021 | RCV003937542.1 |
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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Likely benign
(Jun 24, 2013)
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criteria provided, single submitter
Method: research
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Not provided
Affected status: unknown
Allele origin:
unknown
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000051428.1 First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015 |
Number of individuals with the variant: 2
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Likely benign
(Sep 21, 2015)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1A
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: SCV000745517.1 First in ClinVar: Apr 20, 2018 Last updated: Apr 20, 2018 |
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Benign
(Jul 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Amyloidosis
Arrhythmogenic right ventricular cardiomyopathy
Affected status: yes
Allele origin:
germline
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Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Accession: SCV000995391.1
First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019 |
Number of individuals with the variant: 2
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Likely benign
(Oct 02, 2019)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605387.3
First in ClinVar: Jun 01, 2016 Last updated: Jan 26, 2021 |
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Likely benign
(Feb 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002103687.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
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Likely benign
(Nov 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000737175.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Number of individuals with the variant: 1
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Likely benign
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Loeys-Dietz syndrome 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000646392.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
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Likely benign
(Feb 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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TMPO-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004755072.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Uncertain significance
(Aug 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Primary dilated cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Phosphorus, Inc.
Accession: SCV000679888.1
First in ClinVar: Jan 28, 2018 Last updated: Jan 28, 2018 |
Number of individuals with the variant: 1
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Likely benign
(May 26, 2016)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1A
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000744068.1 First in ClinVar: Apr 20, 2018 Last updated: Apr 20, 2018 |
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Likely benign
(Feb 15, 2022)
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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: SCV000616896.4
First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 24375709, 23861362, 28074886)
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Uncertain significance
(Mar 20, 2014)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280495.1
First in ClinVar: Jun 01, 2016 Last updated: Jun 01, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Pro426Leu (P426L; c.1277 C>T) in the TMPO gene We consider this a Variant of Unknown Significance (VUS)-Probably Benign, given that it has only been reported in the general population and not in any patients with cardiomyopathy. Furthermore, the TMPO gene has been associated in just one family with a disease of the heart muscle known as dilated cardiomyopathy (DCM). It might rightly be called a “gene of uncertain significance” given that only this one variant in one family has been reported: Arg690Cys in two brothers with DCM (Taylor et al. 2005; HGMD). That same variant, Arg690Cys, is present in the NHLBI Exome Sequencing Project (ESP) dataset in 4 Caucasian and 4 African-American individuals, raising the possibility that it is a rare benign variant. The specific variant found in our patient Pro426Leu, has not been reported in the scientific literature as a disease-causing mutation nor as a benign polymorphism to our knowledge. This is a conservative amino acid substitution in which a non-polar Proline is replaced by a non-polar Leucine at a residue that is conserved across species. In silico analysis with PolyPhen-2 predicts the variant to be “probably damaging” with a score of 1.0. The Pro426Leu variant has been observed in 16 out of ~7500 individuals from population datasets. It was found in 2 individuals from Finland in the 1000 Genomes data. It was also found in 13 Caucasian and 1 African-American individuals in the NHLBI Exome Sequencing Project (ESP) dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of March 20, 2014). This represents an allele frequency of 0.15% among Caucasians in the ESP. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. (less)
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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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Psychological adaptation to molecular autopsy findings following sudden cardiac death in the young. | Bates K | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30327538 |
Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases. | Neubauer J | European journal of human genetics : EJHG | 2017 | PMID: 28074886 |
Integrated analysis of germline and somatic variants in ovarian cancer. | Kanchi KL | Nature communications | 2014 | PMID: 24448499 |
Contribution of SUN1 mutations to the pathomechanism in muscular dystrophies. | Li P | Human mutation | 2014 | PMID: 24375709 |
Interpreting secondary cardiac disease variants in an exome cohort. | Ng D | Circulation. Cardiovascular genetics | 2013 | PMID: 23861362 |
Text-mined citations for rs141443652 ...
HelpRecord last updated Apr 15, 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.