ClinVar Genomic variation as it relates to human health
NM_001018005.2(TPM1):c.725C>T (p.Ala242Val)
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.725C>T (p.Ala242Val)
Variation ID: 43437 Accession: VCV000043437.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q22.2 15: 63062598 (GRCh38) [ NCBI UCSC ] 15: 63354797 (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 May 29, 2016 Feb 14, 2024 Dec 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001018005.2:c.725C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001018005.1:p.Ala242Val missense NM_000366.6:c.725C>T NP_000357.3:p.Ala242Val missense NM_001018004.2:c.725C>T NP_001018004.1:p.Ala242Val missense NM_001018006.2:c.725C>T NP_001018006.1:p.Ala242Val missense NM_001018007.2:c.725C>T NP_001018007.1:p.Ala242Val missense NM_001018008.2:c.617C>T NP_001018008.1:p.Ala206Val missense NM_001018020.2:c.725C>T NP_001018020.1:p.Ala242Val missense NM_001301244.2:c.725C>T NP_001288173.1:p.Ala242Val missense NM_001301289.2:c.617C>T NP_001288218.1:p.Ala206Val missense NM_001330344.2:c.617C>T NP_001317273.1:p.Ala206Val missense NM_001330346.2:c.617C>T NP_001317275.1:p.Ala206Val missense NM_001330351.2:c.617C>T NP_001317280.1:p.Ala206Val missense NM_001365776.1:c.725C>T NP_001352705.1:p.Ala242Val missense NM_001365777.1:c.725C>T NP_001352706.1:p.Ala242Val missense NM_001365778.1:c.851C>T NP_001352707.1:p.Ala284Val missense NM_001365779.1:c.725C>T NP_001352708.1:p.Ala242Val missense NM_001365780.1:c.617C>T NP_001352709.1:p.Ala206Val missense NM_001365781.2:c.617C>T NP_001352710.1:p.Ala206Val missense NM_001365782.1:c.617C>T NP_001352711.1:p.Ala206Val missense NC_000015.10:g.63062598C>T NC_000015.9:g.63354797C>T NG_007557.1:g.24960C>T LRG_387:g.24960C>T LRG_387t1:c.725C>T LRG_387p1:p.Ala242Val - Protein change
- A242V, A206V, A284V
- Other names
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- Canonical SPDI
- NC_000015.10:63062597: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), exomes 0.00000
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 |
796 | 847 |
Conditions - Germline
Condition
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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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no classifications from unflagged records (1) |
no classifications from unflagged records
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Apr 14, 2023 | RCV000036357.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 19, 2023 | RCV001237828.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 17, 2020 | RCV001588845.1 | |
Likely pathogenic (2) |
no assertion criteria provided
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- | RCV001699184.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 25, 2023 | RCV003343608.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 1, 2023 | RCV003319174.1 |
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
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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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Likely pathogenic
(Jul 17, 2020)
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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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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV001815800.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
The heterozygous c.725C>T (p.Ala242Val) variant identified in the TPM1 gene substitutes a well conserved Alanine for Valine at amino acid 242/285 (exon 8/10). This variant … (more)
The heterozygous c.725C>T (p.Ala242Val) variant identified in the TPM1 gene substitutes a well conserved Alanine for Valine at amino acid 242/285 (exon 8/10). This variant is absent from gnomAD(v3.0) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Deleterious (Provean; score:-3.3) and Damaging (SIFT; score:0.00) to the function of the canonical transcript. This variant is reported in ClinVar as a Variant of Uncertain Significance (VarID:43437), and has been identified in several individuals in the literature with left ventricular non-compaction [PMID:24691700; PMID:30371277; PMID:28798025] and dilated cardiomyopathy [PMID:27532257; PMID:24503780; PMID:30847666]. Given its absence in population databases, in silico prediction of damaging effect to protein function, and its observation in several affected individuals in the literature, the heterozygous c.725C>T (p.Ala242Val) variant identified in the TPM1 gene is reported as Likely Pathogenic. (less)
Clinical Features:
Primary dilated cardiomyopathy (present) , Recurrent infections (present) , Chronic diarrhea (present) , Anemia (present)
Secondary finding: no
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Likely pathogenic
(Jun 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Primary dilated cardiomyopathy
Affected status: yes
Allele origin:
germline
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Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University
Accession: SCV003932421.1
First in ClinVar: Aug 05, 2023 Last updated: Aug 05, 2023 |
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Likely pathogenic
(Aug 25, 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: SCV004074904.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The p.A242V variant (also known as c.725C>T), located in coding exon 8 of the TPM1 gene, results from a C to T substitution at nucleotide … (more)
The p.A242V variant (also known as c.725C>T), located in coding exon 8 of the TPM1 gene, results from a C to T substitution at nucleotide position 725. The alanine at codon 242 is replaced by valine, an amino acid with similar properties. This variant has been detected in several unrelated individuals with dilated cardiomyopathy (DCM) and/or left ventricular noncompaction cardiomyopathy (LVNC), including a reported de novo occurrence and reported segregation with disease in a family (Pugh TJ et al. Genet Med, 2014 Aug;16:601-8; Tian T et al. Heart Vessels, 2015 Mar;30:258-64; Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Khan RS et al. J Am Heart Assoc, 2022 Jan;11:e022854; van der Meulen MH et al. Circ Genom Precis Med, 2022 Oct;15:e002981; Meshkov AN et al. Front Cardiovasc Med, 2023 May;10:1205787). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Dec 19, 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: SCV001410608.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 242 of the TPM1 protein (p.Ala242Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 242 of the TPM1 protein (p.Ala242Val). This variant is present in population databases (rs397516387, gnomAD 0.0009%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or left ventricular noncompaction (PMID: 24691700, 27532257, 30847666, 34935411; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 43437). 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. For these reasons, this variant has been classified as Pathogenic. (less)
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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, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001926060.1 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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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001963059.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Uncertain significance
(Aug 12, 2020)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Older claim that does not account for recent evidence
Source: ClinGen
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060009.7
First in ClinVar: May 03, 2013 Last updated: May 29, 2021 |
Comment:
The p.Ala242Val variant in TPM1 has been identified in one individual with LVNC (Tian 2015 PMID: 24691700), one individual with DCM and segregated with disease … (more)
The p.Ala242Val variant in TPM1 has been identified in one individual with LVNC (Tian 2015 PMID: 24691700), one individual with DCM and segregated with disease in one family member, but was also present in one unaffected family member (LMM data). This variant has also been identified in 1 of 113742 European alleles in gnomAD. Computational predictors predict that the variant is damaging. The residue is entirely conserved and no species harbor the variant amino acid. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3 (less)
Number of individuals with the variant: 3
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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Genetic landscape in Russian patients with familial left ventricular noncompaction. | Meshkov AN | Frontiers in cardiovascular medicine | 2023 | PMID: 37342443 |
Genetic Evaluation of A Nation-Wide Dutch Pediatric DCM Cohort: The Use of Genetic Testing in Risk Stratification. | van der Meulen MH | Circulation. Genomic and precision medicine | 2022 | PMID: 36178741 |
Genotype and Cardiac Outcomes in Pediatric Dilated Cardiomyopathy. | Khan RS | Journal of the American Heart Association | 2022 | PMID: 34935411 |
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 |
Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction. | Miszalski-Jamka K | Circulation. Cardiovascular genetics | 2017 | PMID: 28798025 |
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 |
A low prevalence of sarcomeric gene variants in a Chinese cohort with left ventricular non-compaction. | Tian T | Heart and vessels | 2015 | PMID: 24691700 |
The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. | Pugh TJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24503780 |
Text-mined citations for rs397516387 ...
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.