ClinVar Genomic variation as it relates to human health
NM_001032283.3(TMPO):c.565+2487C>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(7); Likely benign(1)
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+2487C>T
Variation ID: 12707 Accession: VCV000012707.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q23.1 12: 98534325 (GRCh38) [ NCBI UCSC ] 12: 98928103 (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 4, 2015 Mar 16, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001032283.3:c.565+2487C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001032284.3:c.565+2487C>T intron variant NM_001307975.2:c.565+2487C>T intron variant NM_003276.2:c.2068C>T NP_003267.1:p.Arg690Cys missense NC_000012.12:g.98534325C>T NC_000012.11:g.98928103C>T NG_021393.1:g.23753C>T LRG_443:g.23753C>T LRG_443t2:c.2068C>T LRG_443p2:p.Arg690Cys P42166:p.Arg690Cys - Protein change
- R690C
- Other names
- -
- Canonical SPDI
- NC_000012.12:98534324: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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0.01138 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.01508
The Genome Aggregation Database (gnomAD) 0.00576
1000 Genomes Project 0.01138
Trans-Omics for Precision Medicine (TOPMed) 0.01156
The Genome Aggregation Database (gnomAD), exomes 0.01875
1000 Genomes Project 30x 0.01249
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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Uncertain significance (2) |
criteria provided, single submitter
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Mar 18, 2016 | RCV000013544.33 | |
Benign (3) |
criteria provided, multiple submitters, no conflicts
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Feb 20, 2017 | RCV000037751.17 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 24, 2013 | RCV000172599.9 | |
Benign (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV000231421.18 | |
Benign (1) |
criteria provided, single submitter
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- | RCV001258228.10 | |
Benign (1) |
criteria provided, single submitter
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Nov 22, 2023 | RCV001810855.16 | |
Benign (1) |
criteria provided, single submitter
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Sep 18, 2015 | RCV002310628.8 | |
Benign (1) |
criteria provided, single submitter
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Jul 10, 2019 | RCV003904834.1 |
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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Cardiomyopathy, dilated
Affected status: unknown
Allele origin:
unknown
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000054804.1 First in ClinVar: Jun 04, 2015 Last updated: Jun 04, 2015 |
Number of individuals with the variant: 1
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Uncertain significance
(Mar 18, 2016)
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criteria provided, single submitter
Method: reference population
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Dilated cardiomyopathy 1A
Affected status: unknown
Allele origin:
germline
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Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Accession: SCV000267531.1
First in ClinVar: Apr 21, 2017 Last updated: Apr 21, 2017 |
Number of individuals with the variant: 4
Age: 40-69 years
Ethnicity/Population group: East Asian
Geographic origin: South Korean
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Benign
(Feb 20, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000514912.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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Benign
(Sep 18, 2015)
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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: SCV000318751.6
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA … (more)
This alteration is classified as 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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Benign
(Oct 19, 2012)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061413.6
First in ClinVar: May 03, 2013 Last updated: Mar 08, 2017 |
Comment:
Arg690Cys in exon 4 of TMPO: This variant is not expected to have clinical signi ficance because it has been identified in 11.7% (15/128) of … (more)
Arg690Cys in exon 4 of TMPO: This variant is not expected to have clinical signi ficance because it has been identified in 11.7% (15/128) of Mexican American chr omosomes from a broad population by the 1000 Genomes project (dbSNP rs17028450). This variant has been previously reported in 2 siblings with DCM (Taylor 2005). (less)
Number of individuals with the variant: 14
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Benign
(-)
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criteria provided, single submitter
Method: research
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Hypertrophic cardiomyopathy 25
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001435130.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The heterozygous p.Arg690Cys variant in TCAP has been identified in at least 2 siblings with dilated cardiomyopathy (PMID: 16247757). In vitro functional studies provide some … (more)
The heterozygous p.Arg690Cys variant in TCAP has been identified in at least 2 siblings with dilated cardiomyopathy (PMID: 16247757). In vitro functional studies provide some evidence that the p.Arg690Cys variant may slightly impact protein function (PMID: 16247757). However, these types of assays may not accurately represent biological function. This variant is classified as benign for autosomal dominant dilated cardiomyopathy because it has been identified in >14% of Latino chromosomes and 141 total homozygotes by ExAC (http://gnomad.broadinstitute.org/). (less)
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Benign
(Jan 31, 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: SCV000287931.8
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
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Benign
(Nov 22, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001159171.5
First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024 |
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Benign
(Jul 10, 2019)
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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: SCV004723430.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as 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
(Dec 01, 2005)
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no assertion criteria provided
Method: literature only
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RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033791.4
First in ClinVar: Apr 04, 2013 Last updated: Apr 21, 2017 |
Comment on evidence:
This variant, formerly designated CARDIOMYOPATHY, DILATED, 1T, has been reclassified based on a review of the ExAC database (February 6, 2017) by Hamosh (2017). Taylor … (more)
This variant, formerly designated CARDIOMYOPATHY, DILATED, 1T, has been reclassified based on a review of the ExAC database (February 6, 2017) by Hamosh (2017). Taylor et al. (2005) identified LAP2 as a candidate gene for CMD on the basis of its association with lamin A/C (150330), which is mutated in a form of CMD (CMD1A; 115200). They screened 113 individuals with dilated cardiomyopathy from 88 families for mutation in the LAP2 gene and identified a heterozygous 2068C-T transition in the TMPO gene, predicting an arg690-to-cys (R690C) substitution in the C-terminal domain of the LAP2-alpha protein, in 2 brothers with severe CMD. The older brother first developed cardiac symptoms at age 31 and was diagnosed with CMD at age 33 with a left ventricular ejection fraction of 10%. His brother had symptoms at the age of 22 and was diagnosed at age 24 with an ejection fraction of 32%. The brothers' mother and maternal grandmother reportedly had idiopathic CMD and heart failure, suggesting an autosomal dominant mode of inheritance. The mutation was not found in 300 control chromosomes or in 222 chromosomes of other patients with CMD. Immunofluorescence microscopy in transfected HeLa cells showed localization of mutant LAP2-alpha that was indistinguishable from that of endogenous wildtype protein, indicating that the mutation did not severely impair LAP2-alpha structure and assembly; in addition, expression of mutant LAP2-alpha did not affect distribution of endogenous LAP2-alpha. However, in vitro binding studies using the prelamin A tail (see 150330) demonstrated that the relative amount of bound mutated LAP2-alpha was reduced by 50 to 75% compared to wildtype protein, indicating that the in vitro interaction of R690C mutant LAP2-alpha with the prelamin A tail was significantly reduced compared to wildtype. Hamosh (2017) noted that the R690C variant in the ExAC database (February 6, 2017) had a high allele frequency (1.5%) and was found in 141 homozygotes, suggesting that it is not pathogenic. (less)
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Benign
(Sep 16, 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: SCV000280496.1
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.Arg690Cys (c.2068 C>T) in TMPO (NM_003276.2) This variant has been seen previously with DCM (Taylor et al 2005). However, it was also seen in 13 of 60 indiviudals of Mexican ancestry in 1000 genomes including two homozygous individuals. Our team recently reviewed the evidence that TMPO is implicated in cardiomyopathy and found it to be weak. (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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Thymopoietin (lamina-associated polypeptide 2) gene mutation associated with dilated cardiomyopathy. | Taylor MR | Human mutation | 2005 | PMID: 16247757 |
Hamosh, A. Personal Communication. 2017. Baltimore, Md. | - | - | - | - |
Text-mined citations for rs17028450 ...
HelpRecord last updated Apr 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.