ClinVar Genomic variation as it relates to human health
NM_001276345.2(TNNT2):c.547C>T (p.Arg183Trp)
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_001276345.2(TNNT2):c.547C>T (p.Arg183Trp)
Variation ID: 228409 Accession: VCV000228409.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q32.1 1: 201363349 (GRCh38) [ NCBI UCSC ] 1: 201332477 (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 28, 2024 Oct 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001276345.2:c.547C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001263274.1:p.Arg183Trp missense NM_000364.4:c.547C>T NP_000355.2:p.Arg183Trp missense NM_001001430.3:c.517C>T NP_001001430.1:p.Arg173Trp missense NM_001001431.3:c.517C>T NP_001001431.1:p.Arg173Trp missense NM_001001432.3:c.502C>T NP_001001432.1:p.Arg168Trp missense NM_001276346.2:c.427C>T NP_001263275.1:p.Arg143Trp missense NM_001276347.2:c.517C>T NP_001263276.1:p.Arg173Trp missense NC_000001.11:g.201363349G>A NC_000001.10:g.201332477G>A NG_007556.1:g.19329C>T LRG_431:g.19329C>T LRG_431t1:c.547C>T LRG_431p1:p.Arg183Trp - Protein change
- R173W, R183W, R143W, R168W
- Other names
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- Canonical SPDI
- NC_000001.11:201363348: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
Help
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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TNNT2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
898 | 916 |
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
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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 (2) |
criteria provided, single submitter
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Jan 5, 2022 | RCV000223699.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 14, 2023 | RCV000474826.8 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2023 | RCV001250182.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 7, 2016 | RCV000223622.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 25, 2020 | RCV002338676.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003454597.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003454596.1 |
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
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
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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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Pathogenic
(Jan 07, 2016)
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criteria provided, single submitter
Method: clinical testing
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Primary dilated cardiomyopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271467.3
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
The p.Arg173Trp variant in TNNT2 has been reported in 3 families with DCM, segre gated with disease in >15 affected relatives (Sun 2012, Merlot 2012, … (more)
The p.Arg173Trp variant in TNNT2 has been reported in 3 families with DCM, segre gated with disease in >15 affected relatives (Sun 2012, Merlot 2012, Campbell 20 13), and was absent from large population studies. In vitro functional studies a lso provide some evidence that this variant may impact protein function (Sun 201 2, Sommese 2013). In summary, this variant meets our criteria to be classified a s pathogenic for DCM in an autosomal dominant manner based on segregation studie s, absence from controls, and functional data. (less)
Number of individuals with the variant: 1
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1D
Affected status: yes
Allele origin:
germline
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Centogene AG - the Rare Disease Company
Accession: SCV001424507.1
First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020 |
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Pathogenic
(Mar 25, 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: SCV002644137.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R173W pathogenic mutation (also known as c.517C>T), located in coding exon 10 of the TNNT2 gene, results from a C to T substitution at … (more)
The p.R173W pathogenic mutation (also known as c.517C>T), located in coding exon 10 of the TNNT2 gene, results from a C to T substitution at nucleotide position 517. The arginine at codon 173 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been detected in several individuals with dilated cardiomyopathy (DCM) and has demonstrated strong segregation with DCM in multiple affected families (Sun N et al. Sci Transl Med, 2012 Apr;4:130ra47; Campbell N et al. PLoS ONE, 2013 Oct;8:e78104; Sousa A et al. Rev Port Cardiol, 2019 02;38:129-139). Studies using induced pluripotent stem cell cardiomyocytes from affected individuals have demonstrated functional impacts (Sun N et al. Sci Transl Med, 2012 Apr;4:130ra47; Sommese RF et al. PLoS ONE, 2013 Dec;8:e83403; Wu H et al. Cell Stem Cell, 2015 Jul;17:89-100; Dai Y et al. Sci Rep, 2020 Jan;10:209). Furthermore, an alternate amino acid substitution at this position, p.R173Q, has also been reported in multiple probands with DCM and has been shown to segregate with disease (Van Acker H et al. Int. J. Cardiol., 2010 Oct;144:307-9; Lakdawala NK et al. J. Card. Fail., 2012 Apr;18:296-303; Chauveau S et al. Clin Case Rep, 2017 Jun;5:923-926). 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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Pathogenic
(Jan 05, 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: SCV000616898.4
First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023 |
Comment:
Published functional studies in cardiomyocytes exhibited altered Ca2+ handling and impaired myofilament regulation (Sun et al., 2012); Not observed in large population cohorts (gnomAD); In … (more)
Published functional studies in cardiomyocytes exhibited altered Ca2+ handling and impaired myofilament regulation (Sun et al., 2012); Not observed 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: 32458740, 30624779, 26095046, 26237594, 28315121, 27296521, 24119082, 20800588, 28246128, 24367593, 24205113, 22517884, 27335446, 27237981, 24576884, 25690476, 28573431, 27721795, 25548614, 26265630, 23074333, 30871747, 30565988, 31373515, 31514951, 31931689, 33083013, 33025817, 33087929) (less)
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Pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1D
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004181319.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy, familial restrictive, 3
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004181320.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 2
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004181321.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Oct 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy, familial restrictive, 3
Hypertrophic cardiomyopathy 2 Dilated cardiomyopathy 1D
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000541932.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 173 of the TNNT2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 173 of the TNNT2 protein (p.Arg173Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (DCM) (PMID: 22517884, 24205113). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228409). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNNT2 protein function. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 22517884, 24367593). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Aug 25, 2011)
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no assertion criteria provided
Method: clinical testing
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Not provided
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280527.1
First in ClinVar: Jun 03, 2016 Last updated: Jun 03, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg173Trp (c. 517C>T). At the time of testing this variant was novel (had not been reported in association with cardiomyopathy or as a benign common variant), however it has now been seen in a total of 3 unrelated individuals with cardiomyopathy. An unpublished study conducted in our laboratory demonstrated segregation of the variant in a total of four family members with a DCM diagnosis (Liu et al. 2012 published iPSC studies using this family's DNA). Since testing was completed 3 years ago we contacted the testing lab for an update on this variant and they shared that 1 additional individual (no relation to our proband) tested for DCM was genotype positive for the variant. In addition, Millat et al 2010 reported this variant in a patient with HCM (few clinical details and no segregation data were provided). This is a non conservative amino acid change with a hydrophilic, polar Arginine replaced with a hydrophobic, nonpolar Tryptophan. This variant has not been reported as a benign polymorphism (dbSNP, Google). A variant at the same codon, Arg173Gln, has been seen in at least 3 unrelated families with DCM and/or sudden death (including a SCICD family; please see that variant analysis) and shown to segregate with disease in 5 members of one published family with DCM. Variants in nearby codons (p.Ala172Ser and p.Ser179Phe) have been reported in association with cardiomyopathy (Stefanelli et al 2004 and Ho et al 2000). In silico analysis (PolyPhen) predicts the amino acid change to be damaging to protein structure/function. Arginine is highly conserved at residue 173 across species. This variant was not observed in 335 presumably healthy individuals of mixed ethnicity tested at the testing lab The variant is not listed in dbSNP or 1000 genomes. (less)
Number of individuals with the variant: 3
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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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Troponin destabilization impairs sarcomere-cytoskeleton interactions in iPSC-derived cardiomyocytes from dilated cardiomyopathy patients. | Dai Y | Scientific reports | 2020 | PMID: 31937807 |
Dilated cardiomyopathy mutation (R174W) in troponin T attenuates the length-mediated increase in cross-bridge recruitment and myofilament Ca(2+) sensitivity. | Reda SM | American journal of physiology. Heart and circulatory physiology | 2019 | PMID: 31373515 |
Molecular characterization of Portuguese patients with dilated cardiomyopathy. | Sousa A | Revista portuguesa de cardiologia | 2019 | PMID: 30871747 |
Functional Annotation of TNNT2 Variants of Uncertain Significance With Genome-Edited Cardiomyocytes. | Lv W | Circulation | 2018 | PMID: 30565988 |
A Comprehensive TALEN-Based Knockout Library for Generating Human-Induced Pluripotent Stem Cell-Based Models for Cardiovascular Diseases. | Karakikes I | Circulation research | 2017 | PMID: 28246128 |
Epigenetic Regulation of Phosphodiesterases 2A and 3A Underlies Compromised β-Adrenergic Signaling in an iPSC Model of Dilated Cardiomyopathy. | Wu H | Cell stem cell | 2015 | PMID: 26095046 |
Effects of troponin T cardiomyopathy mutations on the calcium sensitivity of the regulated thin filament and the actomyosin cross-bridge kinetics of human β-cardiac myosin. | Sommese RF | PloS one | 2013 | PMID: 24367593 |
Whole exome sequencing identifies a troponin T mutation hot spot in familial dilated cardiomyopathy. | Campbell N | PloS one | 2013 | PMID: 24205113 |
Poor prognosis of rare sarcomeric gene variants in patients with dilated cardiomyopathy. | Merlo M | Clinical and translational science | 2013 | PMID: 24119082 |
Cardiac structural and sarcomere genes associated with cardiomyopathy exhibit marked intolerance of genetic variation. | Pan S | Circulation. Cardiovascular genetics | 2012 | PMID: 23074333 |
Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy. | Sun N | Science translational medicine | 2012 | PMID: 22517884 |
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Text-mined citations for rs727503512 ...
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.