ClinVar Genomic variation as it relates to human health
NM_001018005.2(TPM1):c.160G>A (p.Glu54Lys)
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.
Pathogenic(1); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001018005.2(TPM1):c.160G>A (p.Glu54Lys)
Variation ID: 12458 Accession: VCV000012458.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q22.2 15: 63044072 (GRCh38) [ NCBI UCSC ] 15: 63336271 (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 Apr 4, 2013 Feb 14, 2024 Mar 5, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001018005.2:c.160G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001018005.1:p.Glu54Lys missense NM_000366.6:c.160G>A NP_000357.3:p.Glu54Lys missense NM_001018004.2:c.160G>A NP_001018004.1:p.Glu54Lys missense NM_001018006.2:c.160G>A NP_001018006.1:p.Glu54Lys missense NM_001018007.2:c.240+241G>A intron variant NM_001018020.2:c.240+241G>A intron variant NM_001301244.2:c.240+241G>A intron variant NM_001365776.1:c.160G>A NP_001352705.1:p.Glu54Lys missense NM_001365777.1:c.160G>A NP_001352706.1:p.Glu54Lys missense NM_001365778.1:c.286G>A NP_001352707.1:p.Glu96Lys missense NM_001365779.1:c.160G>A NP_001352708.1:p.Glu54Lys missense NC_000015.10:g.63044072G>A NC_000015.9:g.63336271G>A NG_007557.1:g.6434G>A LRG_387:g.6434G>A LRG_387t1:c.160G>A LRG_387p1:p.Glu54Lys P09493:p.Glu54Lys - Protein change
- E54K, E96K
- Other names
- p.E54K:GAA>AAA
- Canonical SPDI
- NC_000015.10:63044071:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- functional variant Sequence Ontology [SO:0001536]
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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 |
796 | 847 |
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
Help
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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Pathogenic (2) |
no assertion criteria provided
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Apr 1, 2001 | RCV000013274.24 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 18, 2018 | RCV000159370.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 5, 2020 | RCV001317675.4 |
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
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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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Pathogenic
(Oct 06, 2016)
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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: SCV000209316.12
First in ClinVar: Feb 24, 2015 Last updated: Dec 06, 2016 |
Comment:
The E54K variant in the TPM1 gene has been reported previously in a patient with DCM, and was not reported in 320 control alleles (Olson … (more)
The E54K variant in the TPM1 gene has been reported previously in a patient with DCM, and was not reported in 320 control alleles (Olson T et al., 2011). Functional studies show that E54K decreases calcium sensitivity, reduces actin binding, and results in decreased contractility leading to cardiomyopathy pehnotype (Mirza M et al., 2005; Borovikov Y et al., 2009; Memo M et al., 2013). The E54K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, the E54K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is completely conserved across species. Moreover, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, pathogenic variants in nearby residues (D58H, E62Q, A63V) have been reported in association with HCM, further supporting the functional importance of this region of the protein. In summary, E54K in the TPM1 gene is interpreted as a pathogenic variant. (less)
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Likely pathogenic
(Oct 18, 2018)
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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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Blueprint Genetics
Accession: SCV000928000.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019 |
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Uncertain significance
(Mar 05, 2020)
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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: SCV001508345.4
First in ClinVar: Mar 14, 2021 Last updated: Feb 14, 2024 |
Comment:
This variant has been observed in individual(s) with clinical features of dilated cardiomyopathy (PMID: 11273725). ClinVar contains an entry for this variant (Variation ID: 12458). … (more)
This variant has been observed in individual(s) with clinical features of dilated cardiomyopathy (PMID: 11273725). ClinVar contains an entry for this variant (Variation ID: 12458). 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. This variant has been reported to affect TPM1 protein function (PMID: 23077624, 19646950, 27878731, 19222994, 17556658, 16043485, 25520664, 23539503). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 54 of the TPM1 protein (p.Glu54Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. (less)
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Pathogenic
(Apr 01, 2001)
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no assertion criteria provided
Method: literature only
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CARDIOMYOPATHY, DILATED, 1Y
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033521.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
In a 27-year-old man with dilated cardiomyopathy (CMD1Y; 611878) who died while awaiting cardiac transplantation, Olson et al. (2001) identified heterozygosity for a G-A transition … (more)
In a 27-year-old man with dilated cardiomyopathy (CMD1Y; 611878) who died while awaiting cardiac transplantation, Olson et al. (2001) identified heterozygosity for a G-A transition in exon 2 of the TPM1 gene, resulting in a glu54-to-lys (E54K) substitution at a highly conserved residue. The mutation was not found in 348 unrelated CMD patients or 160 unrelated controls. (less)
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not provided
(Apr 15, 2012)
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no classification provided
Method: curation
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Dilated cardiomyopathy 1Y
Affected status: not provided
Allele origin:
germline
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Leiden Muscular Dystrophy (TPM1)
Accession: SCV000045876.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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has functional consequence
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Leiden Muscular Dystrophy (TPM1)
Accession: SCV000045876.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Effect of Cardiomyopathic Mutations in Tropomyosin on Calcium Regulation of the Actin-Myosin Interaction in Skeletal Muscle. | Kopylova GV | Bulletin of experimental biology and medicine | 2016 | PMID: 27878731 |
Structural and protein interaction effects of hypertrophic and dilated cardiomyopathic mutations in alpha-tropomyosin. | Chang AN | Frontiers in physiology | 2014 | PMID: 25520664 |
Familial dilated cardiomyopathy mutations uncouple troponin I phosphorylation from changes in myofibrillar Ca²⁺ sensitivity. | Memo M | Cardiovascular research | 2013 | PMID: 23539503 |
DCM-related tropomyosin mutants E40K/E54K over-inhibit the actomyosin interaction and lead to a decrease in the number of cycling cross-bridges. | Bai F | PloS one | 2012 | PMID: 23077624 |
Dilated cardiomyopathy mutations in alpha-tropomyosin inhibit its movement during the ATPase cycle. | Borovikov YS | Biochemical and biophysical research communications | 2009 | PMID: 19222994 |
Dilated cardiomyopathy mutant tropomyosin mice develop cardiac dysfunction with significantly decreased fractional shortening and myofilament calcium sensitivity. | Rajan S | Circulation research | 2007 | PMID: 17556658 |
Functional consequences of hypertrophic and dilated cardiomyopathy-causing mutations in alpha-tropomyosin. | Chang AN | The Journal of biological chemistry | 2005 | PMID: 16043485 |
Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy. | Olson TM | Journal of molecular and cellular cardiology | 2001 | PMID: 11273725 |
Text-mined citations for rs104894505 ...
HelpRecord last updated Feb 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.