ClinVar Genomic variation as it relates to human health
NM_001018005.2(TPM1):c.250G>A (p.Asp84Asn)
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_001018005.2(TPM1):c.250G>A (p.Asp84Asn)
Variation ID: 264474 Accession: VCV000264474.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q22.2 15: 63056994 (GRCh38) [ NCBI UCSC ] 15: 63349193 (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 Dec 19, 2017 May 1, 2024 Sep 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001018005.2:c.250G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001018005.1:p.Asp84Asn missense NM_000366.6:c.250G>A NP_000357.3:p.Asp84Asn missense NM_001018004.2:c.250G>A NP_001018004.1:p.Asp84Asn missense NM_001018006.2:c.250G>A NP_001018006.1:p.Asp84Asn missense NM_001018007.2:c.250G>A NP_001018007.1:p.Asp84Asn missense NM_001018008.2:c.142G>A NP_001018008.1:p.Asp48Asn missense NM_001018020.2:c.250G>A NP_001018020.1:p.Asp84Asn missense NM_001301244.2:c.250G>A NP_001288173.1:p.Asp84Asn missense NM_001301289.2:c.142G>A NP_001288218.1:p.Asp48Asn missense NM_001330344.2:c.142G>A NP_001317273.1:p.Asp48Asn missense NM_001330346.2:c.142G>A NP_001317275.1:p.Asp48Asn missense NM_001330351.2:c.142G>A NP_001317280.1:p.Asp48Asn missense NM_001365776.1:c.250G>A NP_001352705.1:p.Asp84Asn missense NM_001365777.1:c.250G>A NP_001352706.1:p.Asp84Asn missense NM_001365778.1:c.376G>A NP_001352707.1:p.Asp126Asn missense NM_001365779.1:c.250G>A NP_001352708.1:p.Asp84Asn missense NM_001365780.1:c.142G>A NP_001352709.1:p.Asp48Asn missense NM_001365781.2:c.142G>A NP_001352710.1:p.Asp48Asn missense NM_001365782.1:c.142G>A NP_001352711.1:p.Asp48Asn missense NC_000015.10:g.63056994G>A NC_000015.9:g.63349193G>A NG_007557.1:g.19356G>A LRG_387:g.19356G>A LRG_387t1:c.250G>A LRG_387p1:p.Asp84Asn - Protein change
- D84N, D126N, D48N
- Other names
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- Canonical SPDI
- NC_000015.10:63056993:G:A
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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), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
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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TPM1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
852 | 900 |
Conditions - Germline
Condition
Help
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
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 pathogenic (1) |
criteria provided, single submitter
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Mar 1, 2017 | RCV000242724.4 | |
Pathogenic/Likely pathogenic (3) |
no assertion criteria provided
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- | RCV001699094.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 6, 2023 | RCV002518731.3 |
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 pathogenic
(Mar 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000320443.7
First in ClinVar: Oct 03, 2016 Last updated: May 01, 2024 |
Comment:
The p.D84N variant (also known as c.250G>A), located in coding exon 3 of the TPM1 gene, results from a G to A substitution at nucleotide … (more)
The p.D84N variant (also known as c.250G>A), located in coding exon 3 of the TPM1 gene, results from a G to A substitution at nucleotide position 250. The aspartic acid at codon 84 is replaced by asparagine, an amino acid with highly similar properties. In one family, this variant was observed to co-segregate with dilated cardiomyopathy (DCM) (van de Meerakker JB et al. Biochim Biophys Acta. 2013;1833(4):833-9). In the same study, in vitro functional analysis indicated this variant would interfere with the electrostatic interaction between tropomyosin and the actin molecule in the presence of Ca2+ resulting in weakened binding capacity. Similar findings were observed in other in vitro functional studies in which disturbance of the electrostatic interaction would lead to decreased Ca2+ sensitivity and therefore a hypotonic response and reduced cardiac contractile function (Orzechowski M et al. Arch Biochem Biophys. 2014;564:89-99; Gupte TM et al. J Biol Chem. 2015;290(11):7003-15). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Likely pathogenic
(Sep 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003441690.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 23147248, 29447731, 30847666). It has also been observed to segregate with disease in … (more)
This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 23147248, 29447731, 30847666). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 264474). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TPM1 function (PMID: 23147248, 25241052, 25548289). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is present in population databases (rs754664923, gnomAD 0.0009%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 84 of the TPM1 protein (p.Asp84Asn). (less)
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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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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001922419.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
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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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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953677.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001968484.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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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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Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. | van Lint FHM | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2019 | PMID: 30847666 |
Genetics, Clinical Features, and Long-Term Outcome of Noncompaction Cardiomyopathy. | van Waning JI | Journal of the American College of Cardiology | 2018 | PMID: 29447731 |
Mechanistic heterogeneity in contractile properties of α-tropomyosin (TPM1) mutants associated with inherited cardiomyopathies. | Gupte TM | The Journal of biological chemistry | 2015 | PMID: 25548289 |
Energy landscapes reveal the myopathic effects of tropomyosin mutations. | Orzechowski M | Archives of biochemistry and biophysics | 2014 | PMID: 25241052 |
A novel alpha-tropomyosin mutation associates with dilated and non-compaction cardiomyopathy and diminishes actin binding. | van de Meerakker JB | Biochimica et biophysica acta | 2013 | PMID: 23147248 |
Text-mined citations for rs754664923 ...
HelpRecord last updated Sep 29, 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.