ClinVar Genomic variation as it relates to human health
NM_001018005.2(TPM1):c.252C>G (p.Asp84Glu)
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.252C>G (p.Asp84Glu)
Variation ID: 43408 Accession: VCV000043408.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q22.2 15: 63056996 (GRCh38) [ NCBI UCSC ] 15: 63349195 (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 Jan 31, 2015 Apr 20, 2024 Nov 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001018005.2:c.252C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001018005.1:p.Asp84Glu missense NM_000366.6:c.252C>G NP_000357.3:p.Asp84Glu missense NM_001018004.2:c.252C>G NP_001018004.1:p.Asp84Glu missense NM_001018006.2:c.252C>G NP_001018006.1:p.Asp84Glu missense NM_001018007.2:c.252C>G NP_001018007.1:p.Asp84Glu missense NM_001018008.2:c.144C>G NP_001018008.1:p.Asp48Glu missense NM_001018020.2:c.252C>G NP_001018020.1:p.Asp84Glu missense NM_001301244.2:c.252C>G NP_001288173.1:p.Asp84Glu missense NM_001301289.2:c.144C>G NP_001288218.1:p.Asp48Glu missense NM_001330344.2:c.144C>G NP_001317273.1:p.Asp48Glu missense NM_001330346.2:c.144C>G NP_001317275.1:p.Asp48Glu missense NM_001330351.2:c.144C>G NP_001317280.1:p.Asp48Glu missense NM_001365776.1:c.252C>G NP_001352705.1:p.Asp84Glu missense NM_001365777.1:c.252C>G NP_001352706.1:p.Asp84Glu missense NM_001365778.1:c.378C>G NP_001352707.1:p.Asp126Glu missense NM_001365779.1:c.252C>G NP_001352708.1:p.Asp84Glu missense NM_001365780.1:c.144C>G NP_001352709.1:p.Asp48Glu missense NM_001365781.2:c.144C>G NP_001352710.1:p.Asp48Glu missense NM_001365782.1:c.144C>G NP_001352711.1:p.Asp48Glu missense NC_000015.10:g.63056996C>G NC_000015.9:g.63349195C>G NG_007557.1:g.19358C>G LRG_387:g.19358C>G LRG_387t1:c.252C>G LRG_387p1:p.Asp84Glu - Protein change
- D84E, D48E, D126E
- Other names
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- Canonical SPDI
- NC_000015.10:63056995:C:G
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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.
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 |
848 | 898 |
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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Uncertain significance (1) |
criteria provided, single submitter
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May 10, 2012 | RCV000036320.5 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 8, 2023 | RCV001852754.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 8, 2023 | RCV001185543.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 15, 2021 | RCV002482973.1 |
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
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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
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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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Uncertain significance
(Nov 08, 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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Invitae
Accession: SCV002220306.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 84 of the TPM1 … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 84 of the TPM1 protein (p.Asp84Glu). This variant is present in population databases (rs369617788, gnomAD 0.0009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 43408). 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 tolerated. This variant disrupts the p.Asp84 amino acid residue in TPM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23147248, 25548289). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Mar 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001351789.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces aspartic acid with glutamic acid at codon 84 of the TPM1 protein. Computational prediction suggests that this variant may not impact … (more)
This missense variant replaces aspartic acid with glutamic acid at codon 84 of the TPM1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 1/251466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Asp84Asn, is considered to be disease-causing (ClinVar variation ID: 264474), suggesting that aspartic acid at this position is important for TPM1 protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(May 10, 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: SCV000059972.6
First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015 |
Comment:
The Asp84Glu variant has not been reported in the literature. It has been identi fied in one individual with HCM by our laboratory, but did … (more)
The Asp84Glu variant has not been reported in the literature. It has been identi fied in one individual with HCM by our laboratory, but did not segregate in a re portedly affected family member. Aspartic acid at position 84 is conserved in ma mmals, though chicken has a glutamic acid (Glu; this variant) at this position. This variant was predicted to be pathogenic using a computational tool, which wa s validated by our laboratory using a set of cardiomyopathy variants with well-e stablished clinical significance. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). Additional information is needed t o fully assess the clinical significance of the Asp84Glu variant. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Nov 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 3
Dilated cardiomyopathy 1Y
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002790107.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain Significance
(Apr 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004815440.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces aspartic acid with glutamic acid at codon 84 of the TPM1 protein. Computational prediction suggests that this variant may not impact … (more)
This missense variant replaces aspartic acid with glutamic acid at codon 84 of the TPM1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 1/251466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Asp84Asn, is considered to be disease-causing (ClinVar variation ID: 264474), suggesting that aspartic acid at this position is important for TPM1 protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 2
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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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Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
Mechanistic heterogeneity in contractile properties of α-tropomyosin (TPM1) mutants associated with inherited cardiomyopathies. | Gupte TM | The Journal of biological chemistry | 2015 | PMID: 25548289 |
Text-mined citations for rs369617788 ...
HelpRecord last updated Jun 23, 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.