ClinVar Genomic variation as it relates to human health
NM_001018005.2(TPM1):c.533G>A (p.Arg178His)
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(2); Likely pathogenic(2); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001018005.2(TPM1):c.533G>A (p.Arg178His)
Variation ID: 43423 Accession: VCV000043423.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q22.2 15: 63060909 (GRCh38) [ NCBI UCSC ] 15: 63353108 (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 Feb 28, 2024 Jul 3, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001018005.2:c.533G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001018005.1:p.Arg178His missense NM_000366.6:c.533G>A NP_000357.3:p.Arg178His missense NM_001018004.2:c.533G>A NP_001018004.1:p.Arg178His missense NM_001018006.2:c.533G>A NP_001018006.1:p.Arg178His missense NM_001018007.2:c.533G>A NP_001018007.1:p.Arg178His missense NM_001018008.2:c.425G>A NP_001018008.1:p.Arg142His missense NM_001018020.2:c.533G>A NP_001018020.1:p.Arg178His missense NM_001301244.2:c.533G>A NP_001288173.1:p.Arg178His missense NM_001301289.2:c.425G>A NP_001288218.1:p.Arg142His missense NM_001330344.2:c.425G>A NP_001317273.1:p.Arg142His missense NM_001330346.2:c.425G>A NP_001317275.1:p.Arg142His missense NM_001330351.2:c.425G>A NP_001317280.1:p.Arg142His missense NM_001365776.1:c.533G>A NP_001352705.1:p.Arg178His missense NM_001365777.1:c.533G>A NP_001352706.1:p.Arg178His missense NM_001365778.1:c.659G>A NP_001352707.1:p.Arg220His missense NM_001365779.1:c.533G>A NP_001352708.1:p.Arg178His missense NM_001365780.1:c.425G>A NP_001352709.1:p.Arg142His missense NM_001365781.2:c.425G>A NP_001352710.1:p.Arg142His missense NM_001365782.1:c.425G>A NP_001352711.1:p.Arg142His missense NC_000015.10:g.63060909G>A NC_000015.9:g.63353108G>A NG_007557.1:g.23271G>A LRG_387:g.23271G>A LRG_387t1:c.533G>A LRG_387p1:p.Arg178His - Protein change
- R178H, R220H, R142H
- Other names
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- Canonical SPDI
- NC_000015.10:63060908:G:A
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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
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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
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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 |
835 | 884 |
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
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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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Dec 7, 2012 | RCV000036341.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 13, 2022 | RCV001344106.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 18, 2021 | RCV001376065.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 18, 2022 | RCV001564674.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 18, 2022 | RCV002345287.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 3, 2023 | RCV003447481.1 |
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
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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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Likely pathogenic
(Feb 18, 2022)
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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: SCV002643261.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R178H variant (also known as c.533G>A), located in coding exon 5 of the TPM1 gene, results from a G to A substitution at nucleotide … (more)
The p.R178H variant (also known as c.533G>A), located in coding exon 5 of the TPM1 gene, results from a G to A substitution at nucleotide position 533. The arginine at codon 178 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in three cases in the literature with left ventricular noncompaction or dilated cardiomyopathy presenting with or progressing to heart failure within the first year of life (Takasaki A et al. Pediatr Res, 2018 11;84:733-742; Farnaes L et al. NPJ Genom Med, 2018 Apr;3:10; Mehaney DA et al. Cardiol Young, 2022 Feb;32:295-300). In addition, this variant was confirmed de novo in a neonate with ascites, diffuse edema, and cardiomegaly with multi-chamber enlargement (Genomic Medicine Lab, University of California San Francisco pers. comm.). 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)), and is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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)
Number of individuals with the variant: 1
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Pathogenic
(Jul 03, 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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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175265.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The TPM1 c.533G>A variant is classified as Pathogenic (PS2, PS3, PS4_Moderate, PM2, PP3) The TPM1 c.533G>A variant is a single nucleotide change in exon 5/10 … (more)
The TPM1 c.533G>A variant is classified as Pathogenic (PS2, PS3, PS4_Moderate, PM2, PP3) The TPM1 c.533G>A variant is a single nucleotide change in exon 5/10 of the TPM1 gene, which is predicted to change the amino acid arginine at position 178 in the protein, to histidine. This variant has been identified as a de novo variant in this patient (PS2). The variant has been reported in greater than 6 probands with a clinical presentation of infant/childhood-onset left ventricular non-compaction/dilated cardiomyopathy/cardiomyopathy (PMID#30188508,29644095,36252119, 34036930) (PS4_Moderate) and is absent from population databases (PM2). Well-established functional studies of this variant in human-induced pluripotent stem cells (cardiomyocyte induced), show a deleterious effect with mis-localisation of tropomyosin 1 resulting in the disruption of the sarcomere and impaired calcium handling (PMID#30188508) (PS3). The variant has been reported in dbSNP (rs397516375), is reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 43423) and is reported as disease causing in HGMD (CM186474). Computational predictions support a deleterious effect on the gene or gene product (PP3). (less)
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Uncertain significance
(Nov 13, 2022)
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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: SCV001538142.4
First in ClinVar: Mar 22, 2021 Last updated: Feb 28, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 43423). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or left ventricular noncompaction … (more)
ClinVar contains an entry for this variant (Variation ID: 43423). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or left ventricular noncompaction (PMID: 29644095, 30188508, 34036930; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 178 of the TPM1 protein (p.Arg178His). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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
(Dec 07, 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: SCV000059993.6
First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015 |
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The Arg178His v ariant in TPM1 has not been reported in the literature nor previously identified by … (more)
Variant classified as Uncertain Significance - Favor Pathogenic. The Arg178His v ariant in TPM1 has not been reported in the literature nor previously identified by our laboratory. This variant has also not been identified in large and broa d European American and African American populations screened by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS) but it remains possible t hat this variant is common in other populations. Arginine (Arg) at position 178 is conserved in evolution and the change to Histidine (His) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. T his tool's pathogenic prediction is estimated to be correct 94% of the time (Jor dan 2011). Although this data supports that the Arg178His variant may be pathoge nic, additional studies are needed to fully assess its clinical significance. (less)
Number of individuals with the variant: 1
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Pathogenic
(Feb 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1Y
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Genomic Medicine Lab, University of California San Francisco
Study: CSER-P3EGS
Accession: SCV001573088.1 First in ClinVar: May 05, 2021 Last updated: May 05, 2021 |
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Likely pathogenic
(Aug 18, 2022)
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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: SCV001787873.3
First in ClinVar: Aug 19, 2021 Last updated: Mar 04, 2023 |
Comment:
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; … (more)
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; Functional studies using human-induced pluripotent stem cells from a patient harboring the p.(R178H) variant showed impaired tropomyosin 1 localization, sarcomere structure, and calcium handling (Takasaki et al., 2018); This variant is associated with the following publications: (PMID: 32600061, 33888711, 34036930, 31019026, 29644095, 30188508) (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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Genetic Basis of Childhood Cardiomyopathy. | Bagnall RD | Circulation. Genomic and precision medicine | 2022 | PMID: 36252119 |
Molecular analysis of dilated and left ventricular noncompaction cardiomyopathies in Egyptian children. | Mehaney DA | Cardiology in the young | 2022 | PMID: 34036930 |
Rapid whole genome sequencing impacts care and resource utilization in infants with congenital heart disease. | Sweeney NM | NPJ genomic medicine | 2021 | PMID: 33888711 |
Increased Burden of Ion Channel Gene Variants Is Related to Distinct Phenotypes in Pediatric Patients With Left Ventricular Noncompaction. | Hirono K | Circulation. Genomic and precision medicine | 2020 | PMID: 32600061 |
Sarcomere gene variants act as a genetic trigger underlying the development of left ventricular noncompaction. | Takasaki A | Pediatric research | 2018 | PMID: 30188508 |
Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization. | Farnaes L | NPJ genomic medicine | 2018 | PMID: 29644095 |
Text-mined citations for rs397516375 ...
HelpRecord last updated Apr 06, 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.