ClinVar Genomic variation as it relates to human health
NM_001018005.2(TPM1):c.548C>T (p.Ala183Val)
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.
Likely pathogenic(3); Uncertain significance(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001018005.2(TPM1):c.548C>T (p.Ala183Val)
Variation ID: 43424 Accession: VCV000043424.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q22.2 15: 63060924 (GRCh38) [ NCBI UCSC ] 15: 63353123 (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 Jul 24, 2016 Feb 20, 2024 Dec 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001018005.2:c.548C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001018005.1:p.Ala183Val missense NM_000366.6:c.548C>T NP_000357.3:p.Ala183Val missense NM_001018004.2:c.548C>T NP_001018004.1:p.Ala183Val missense NM_001018006.2:c.548C>T NP_001018006.1:p.Ala183Val missense NM_001018007.2:c.548C>T NP_001018007.1:p.Ala183Val missense NM_001018008.2:c.440C>T NP_001018008.1:p.Ala147Val missense NM_001018020.2:c.548C>T NP_001018020.1:p.Ala183Val missense NM_001301244.2:c.548C>T NP_001288173.1:p.Ala183Val missense NM_001301289.2:c.440C>T NP_001288218.1:p.Ala147Val missense NM_001330344.2:c.440C>T NP_001317273.1:p.Ala147Val missense NM_001330346.2:c.440C>T NP_001317275.1:p.Ala147Val missense NM_001330351.2:c.440C>T NP_001317280.1:p.Ala147Val missense NM_001365776.1:c.548C>T NP_001352705.1:p.Ala183Val missense NM_001365777.1:c.548C>T NP_001352706.1:p.Ala183Val missense NM_001365778.1:c.674C>T NP_001352707.1:p.Ala225Val missense NM_001365779.1:c.548C>T NP_001352708.1:p.Ala183Val missense NM_001365780.1:c.440C>T NP_001352709.1:p.Ala147Val missense NM_001365781.2:c.440C>T NP_001352710.1:p.Ala147Val missense NM_001365782.1:c.440C>T NP_001352711.1:p.Ala147Val missense NC_000015.10:g.63060924C>T NC_000015.9:g.63353123C>T NG_007557.1:g.23286C>T LRG_387:g.23286C>T LRG_387t1:c.548C>T LRG_387p1:p.Ala183Val - Protein change
- A183V, A225V, A147V
- Other names
- p.A183V:GCT>GTT
- Canonical SPDI
- NC_000015.10:63060923: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
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 |
797 | 846 |
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 (1) |
criteria provided, single submitter
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Oct 7, 2015 | RCV000036342.8 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 10, 2023 | RCV000538013.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 8, 2023 | RCV000620344.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 24, 2023 | RCV000766949.2 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 16, 2023 | RCV001798100.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 2, 2022 | RCV002272038.2 |
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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Uncertain significance
(May 25, 2021)
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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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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002042870.1
First in ClinVar: Dec 29, 2021 Last updated: Dec 29, 2021 |
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Uncertain significance
(Jun 08, 2023)
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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: SCV000740025.5
First in ClinVar: Apr 14, 2018 Last updated: Jul 08, 2023 |
Comment:
The p.A183V variant (also known as c.548C>T), located in coding exon 5 of the TPM1 gene, results from a C to T substitution at nucleotide … (more)
The p.A183V variant (also known as c.548C>T), located in coding exon 5 of the TPM1 gene, results from a C to T substitution at nucleotide position 548. The alanine at codon 183 is replaced by valine, an amino acid with similar properties. This variant has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10:[Epub ahead of print]; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Oct 24, 2023)
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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: SCV000209314.14
First in ClinVar: Feb 24, 2015 Last updated: Nov 25, 2023 |
Comment:
Reported in association with HCM in published literature (Lopes et al., 2015; Alfares et al., 2015; Walsh et al., 2017; Burns et al., 2017; Ross … (more)
Reported in association with HCM in published literature (Lopes et al., 2015; Alfares et al., 2015; Walsh et al., 2017; Burns et al., 2017; Ross et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28790153, 28408708, 28615295, 25351510, 36243179, 25611685, 27532257) (less)
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Uncertain significance
(Oct 07, 2015)
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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: SCV000059994.5
First in ClinVar: May 03, 2013 Last updated: Apr 17, 2019 |
Comment:
The p.Ala183Val variant in TPM1 has been identified by our laboratory in 1 indiv idual with HCM and was absent from large population studies. Computational … (more)
The p.Ala183Val variant in TPM1 has been identified by our laboratory in 1 indiv idual with HCM and was absent from large population studies. Computational predi ction tools and conservation analysis suggest that the p.Ala183Val variant may i mpact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Ala183Val variant is uncertain. (less)
Number of individuals with the variant: 2
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Likely pathogenic
(Jul 25, 2017)
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criteria provided, single submitter
Method: research
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Hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV000996347.2
First in ClinVar: Nov 02, 2019 Last updated: Jan 09, 2020 |
Comment:
The TPM1 Ala183Val has previously been reported in 6 individuals with HCM (Walsh R, et al 2017;SCV000209314 - GeneDx personal communication). We have identified this … (more)
The TPM1 Ala183Val has previously been reported in 6 individuals with HCM (Walsh R, et al 2017;SCV000209314 - GeneDx personal communication). We have identified this variant in 3 probands of European ethnicity; 2 with no family history of disease and 1 with an affected sibling who also harbours this variant. The TPM1 Ala183Val variant is absent in the 1000 genomes project (http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). In silico tools, MutationTaster, PolyPhen-2 and SIFT predict this variant the be deleterious. Based on this information we classify this variant as "likely pathogenic". (less)
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Likely pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 3
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002558017.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0105 - The mechanism of disease for this … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, although it has been suggested that that HCM is caused by gain of function missense variants while DCM is caused by loss of function missense variants (PMID: 31270709). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions but very high conservation. (I) 0600 - Variant is located in the annotated Tropomyosin domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported four times as a VUS and once as likely pathogenic in ClinVar. However, this variant has been reported in at least ten unrelated individuals with HCM (ClinVar, PMID: 27532257, PMID: 28615295, PMID: 25351510). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Uncertain significance
(Mar 16, 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: SCV002052893.2
First in ClinVar: Jan 08, 2022 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces alanine with valine at codon 183 of the TPM1 protein. Computational prediction suggests that this variant may have a deleterious impact … (more)
This missense variant replaces alanine with valine at codon 183 of the TPM1 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least six unrelated individuals and in one family affected with hypertrophic cardiomyopathy (PMID: 25351510, 25611685, 27532257, 28408708, 28615295, 28790153, 33495597). This variant has also been reported in a healthy individual who had a family history of hypertrophic cardiomyopathy (Patel 2018, dissertation, University College London). This variant has been identified in 4/251314 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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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Likely pathogenic
(Dec 10, 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: SCV000623805.4
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 183 of the TPM1 protein (p.Ala183Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 183 of the TPM1 protein (p.Ala183Val). This variant is present in population databases (rs397516376, gnomAD 0.004%). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 28615295; Invitae). ClinVar contains an entry for this variant (Variation ID: 43424). 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. 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. (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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Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. | Harper AR | Nature genetics | 2021 | PMID: 33495597 |
Thin filament dysfunctions caused by mutations in tropomyosin Tpm3.12 and Tpm1.1. | Moraczewska J | Journal of muscle research and cell motility | 2020 | PMID: 31270709 |
Multiple Gene Variants in Hypertrophic Cardiomyopathy in the Era of Next-Generation Sequencing. | Burns C | Circulation. Cardiovascular genetics | 2017 | PMID: 28790153 |
Burden of Recurrent and Ancestral Mutations in Families With Hypertrophic Cardiomyopathy. | Ross SB | Circulation. Cardiovascular genetics | 2017 | PMID: 28615295 |
Nonfamilial Hypertrophic Cardiomyopathy: Prevalence, Natural History, and Clinical Implications. | Ingles J | Circulation. Cardiovascular genetics | 2017 | PMID: 28408708 |
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 |
Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. | Alfares AA | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25611685 |
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
Text-mined citations for rs397516376 ...
HelpRecord last updated Feb 28, 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.