ClinVar Genomic variation as it relates to human health
NM_001018005.2(TPM1):c.842T>C (p.Met281Thr)
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.842T>C (p.Met281Thr)
Variation ID: 31885 Accession: VCV000031885.49
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q22.2 15: 63064133 (GRCh38) [ NCBI UCSC ] 15: 63356332 (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 Apr 15, 2024 Jan 4, 2024 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- M281T, M245T
- Other names
- p.M281T:ATG>ACG
- Canonical SPDI
- NC_000015.10:63064132:T:C
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 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
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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
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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
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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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Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Oct 24, 2023 | RCV000024581.27 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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Aug 27, 2023 | RCV000154219.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 4, 2024 | RCV000232738.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 4, 2020 | RCV000618291.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 7, 2016 | RCV000622737.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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- | RCV001594374.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 13, 2021 | RCV003149577.3 |
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
(Jul 07, 2016)
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criteria provided, single submitter
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000740435.1
First in ClinVar: Apr 15, 2018 Last updated: Apr 15, 2018 |
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1Y
Affected status: yes
Allele origin:
germline
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KTest Genetics, KTest
Accession: SCV001499981.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
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Likely pathogenic
(Sep 13, 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: SCV003837753.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Pathogenic
(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: SCV000209336.16
First in ClinVar: Feb 24, 2015 Last updated: Nov 25, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect as this variant alters the binding affinity of … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect as this variant alters the binding affinity of tropomyosin for actin (Bai et al., 2013; Sequeira et al., 2013; Gupte et al., 2014); 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: 12860912, 20965760, 23508784, 23071391, 18533079, 27532257, 25524337, 21823217, 23700264, 22112859, 21835320, 30297972, 31308319, 32882290, 30240712, 34011823, 25548289, 30847666, 35626289) (less)
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Pathogenic
(Jan 04, 2024)
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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: SCV000285670.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 281 of the TPM1 protein (p.Met281Thr). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 281 of the TPM1 protein (p.Met281Thr). This variant is present in population databases (rs199476321, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12860912, 18533079, 20965760, 21835320, 22112859, 25524337, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 31885). 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. Experimental studies have shown that this missense change affects TPM1 function (PMID: 25548289). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 04, 2020)
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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: SCV000739941.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.M281T pathogenic mutation (also known as c.842T>C), located in coding exon 9 of the TPM1 gene, results from a T to C substitution at … (more)
The p.M281T pathogenic mutation (also known as c.842T>C), located in coding exon 9 of the TPM1 gene, results from a T to C substitution at nucleotide position 842. The methionine at codon 281 is replaced by threonine, an amino acid with some similar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM), and co-segregation was reported in affected family members in some cases (Van Driest SL, Circulation 2003 Jul; 108(4):445-51; Olivotto I, Mayo Clin. Proc. 2008 Jun; 83(6):630-8; Coppini R, J. Am. Coll. Cardiol. 2014 Dec; 64(24):2589-600; Otsuka H, Circ. J. 2012; 76(2):453-61; Walsh R et al. Genet. Med., 2017 02;19:192-203; Tran Vu MT et al. Circ. J., 2019 Aug;83:1908-1916). This variant was also reported in a child with restrictive cardiomyopathy, who had an additional TPM1 variant detected in trans; her mother and maternal uncle were asymptomatic carriers for only p.M281T, although the uncle reportedly showed mild left ventricular hypertrophy (Dorsch LM et al. Int J Cardiol, 2020 Sep;[Epub ahead of print]). In addition, studies suggest this alteration has an impact on protein function, but the clinical relevance of these findings is uncertain (Gupte TM, J. Biol. Chem. 2015 Mar; 290(11):7003-15; Dorsch LM et al. Int J Cardiol, 2020 Sep;[Epub ahead of print]). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(May 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000892133.22
First in ClinVar: Mar 31, 2019 Last updated: Apr 15, 2024 |
Comment:
TPM1: PM2, PM5, PP3, PS3:Supporting, PS4:Supporting
Number of individuals with the variant: 3
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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: SCV001923479.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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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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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: SCV001957811.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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not provided
(Apr 15, 2012)
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no classification provided
Method: curation
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not specified
Affected status: not provided
Allele origin:
germline
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Leiden Muscular Dystrophy (TPM1)
Accession: SCV000045890.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
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Uncertain significance
(Nov 30, 2016)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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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: SCV000203874.5
First in ClinVar: Jan 31, 2015 Last updated: Aug 26, 2019 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 2
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
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: SCV000045890.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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The effect of tropomyosin variants on cardiomyocyte function and structure that underlie different clinical cardiomyopathy phenotypes. | Dorsch LM | International journal of cardiology | 2021 | PMID: 32882290 |
Presence of Hypertrophic Cardiomyopathy Related Gene Mutations and Clinical Manifestations in Vietnamese Patients With Hypertrophic Cardiomyopathy. | Tran Vu MT | Circulation journal : official journal of the Japanese Circulation Society | 2019 | PMID: 31308319 |
The effects of cardiomyopathy-associated mutations in the head-to-tail overlap junction of α-tropomyosin on its properties and interaction with actin. | Matyushenko AM | International journal of biological macromolecules | 2019 | PMID: 30240712 |
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 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Mechanistic heterogeneity in contractile properties of α-tropomyosin (TPM1) mutants associated with inherited cardiomyopathies. | Gupte TM | The Journal of biological chemistry | 2015 | PMID: 25548289 |
Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations. | Coppini R | Journal of the American College of Cardiology | 2014 | PMID: 25524337 |
Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations. | Sequeira V | Circulation research | 2013 | PMID: 23508784 |
Integrative structural modelling of the cardiac thin filament: energetics at the interface and conservation patterns reveal a spotlight on period 2 of tropomyosin. | Margaret Sunitha S | Bioinformatics and biology insights | 2012 | PMID: 23071391 |
Prevalence and distribution of sarcomeric gene mutations in Japanese patients with familial hypertrophic cardiomyopathy. | Otsuka H | Circulation journal : official journal of the Japanese Circulation Society | 2012 | PMID: 22112859 |
Microvascular function is selectively impaired in patients with hypertrophic cardiomyopathy and sarcomere myofilament gene mutations. | Olivotto I | Journal of the American College of Cardiology | 2011 | PMID: 21835320 |
Identification of a novel TPM1 mutation in a family with left ventricular noncompaction and sudden death. | Chang B | Molecular genetics and metabolism | 2011 | PMID: 20965760 |
Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. | Olivotto I | Mayo Clinic proceedings | 2008 | PMID: 18533079 |
Prevalence and spectrum of thin filament mutations in an outpatient referral population with hypertrophic cardiomyopathy. | Van Driest SL | Circulation | 2003 | PMID: 12860912 |
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Text-mined citations for rs199476321 ...
HelpRecord last updated Apr 15, 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.