ClinVar Genomic variation as it relates to human health
NM_001276345.2(TNNT2):c.421C>T (p.Arg141Trp)
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.421C>T (p.Arg141Trp)
Variation ID: 12415 Accession: VCV000012415.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q32.1 1: 201364366 (GRCh38) [ NCBI UCSC ] 1: 201333494 (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 Feb 28, 2024 Apr 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001276345.2:c.421C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001263274.1:p.Arg141Trp missense NM_000364.4:c.421C>T NP_000355.2:p.Arg141Trp missense NM_001001430.3:c.391C>T NP_001001430.1:p.Arg131Trp missense NM_001001431.3:c.391C>T NP_001001431.1:p.Arg131Trp missense NM_001001432.3:c.376C>T NP_001001432.1:p.Arg126Trp missense NM_001276346.2:c.301C>T NP_001263275.1:p.Arg101Trp missense NM_001276347.2:c.391C>T NP_001263276.1:p.Arg131Trp missense NC_000001.11:g.201364366G>A NC_000001.10:g.201333494G>A NG_007556.1:g.18312C>T LRG_431:g.18312C>T LRG_431t1:c.421C>T LRG_431p1:p.Arg141Trp - Protein change
- R131W, R141W, R126W, R101W
- Other names
- p.R131W:CGG>TGG
- Canonical SPDI
- NC_000001.11:201364365: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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
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
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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TNNT2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
898 | 917 |
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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Likely pathogenic (2) |
criteria provided, single submitter
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Apr 11, 2023 | RCV000013226.30 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 30, 2013 | RCV000030567.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 4, 2022 | RCV000159291.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 14, 2023 | RCV000524541.7 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 10, 2023 | RCV000588329.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003450631.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003450630.1 |
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
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
(Sep 30, 2013)
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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: SCV000060239.6
First in ClinVar: Apr 04, 2013 Last updated: Apr 21, 2018 |
Comment:
The Arg131Trp variant in TNNT2 has been identified in 1 individual with LVNC whe re it was reported to have occurred de novo (Klaassen 2008) … (more)
The Arg131Trp variant in TNNT2 has been identified in 1 individual with LVNC whe re it was reported to have occurred de novo (Klaassen 2008) and has now been ide ntified by our laboratory in 2 individuals with DCM. It was not identified in la rge population studies. Additionally, studies have shown that the Arg131Trp vari ant alters calcium binding properties of the thin filaments (Robinson 2007, Lui 2012). However, these in vitro assays may not accurately represent biological fu nction. Arginine (Arg) at position 131 is highly conserved in mammals and across evolutionarily distant species and the change to tryptophan (Trp) was predicted to be pathogenic using a computational tool clinically validated by our laborat ory. This tool's pathogenic prediction is estimated to be correct 94% of the tim e (Jordan 2011). In summary, this variant is likely to be pathogenic, though add itional studies are required to fully establish its clinical significance. (less)
Number of individuals with the variant: 2
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Likely pathogenic
(Jun 22, 2017)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697562.3
First in ClinVar: Mar 17, 2018 Last updated: Dec 11, 2022 |
Comment:
Variant summary: The TNNT2 c.391C>T (p.Arg131Trp) variant results in a non-conservative amino acid substitution located in the tropomyosin binding domain of the protein (Mogensen_2004, Klaassen_2008). … (more)
Variant summary: The TNNT2 c.391C>T (p.Arg131Trp) variant results in a non-conservative amino acid substitution located in the tropomyosin binding domain of the protein (Mogensen_2004, Klaassen_2008). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/116588 control chromosomes at a frequency of 0.0000086, which does not exceed the estimated maximal expected allele frequency of a pathogenic TNNT2 variant (0.000175). This variant has been found in 4 probands (1st with DCM, 2nd with LVNC, 3rd with DCM/LVNC, and 4th with DCM) in the reported literature. In the first family, it was found to co-segregate with DCM in at least two affected members. In second family, the variant was found to be de novo in the affected proband; however, it is not specified whether paternity was confirmed. In the third family, affected mother was available for genotyping but she did not carry the variant. From the results of third family, authors assume the variant either to be VUS or disease-causing having reduced penetrance. The unaffected father in the family was not available for genotyping. Though this lack of co-segregation may indicate that it may not be pathogenic, the possibility that another familial variant was explaining the phenotype in the mother which remained untransmitted in the proband cannot be ruled out. In addition, this variant could have a reduced penetrance and could have been transmitted from the unaffected father, or it could have originated de novo. The variant has also been reported in two patients with DCM by LMM/PH (unpublished findings). Several independent functional studies dating from 2004 to 2016 have demonstrated that this variant results in a depressed myofilament calcium sensitivity in alpha-MHC (myosin heavy chains) thereby inducing a more severe DCM-like contractile phenotype against an alpha-MHC background. These results are consistent with an established molecular mechanism of disease due to an alteration in the contractile dynamics in the presence of mutations in TNNT2. Three diagnostic centers via ClinVar interpret the variant as pathogenic/likely pathogenic, without evidence for independent evaluation. There are also other potentially pathogenic missense variants around this variant (such as such as p.E128K, p.R130C and p.R134G), suggesting a notion that the region may have a functional importance. Taken all evidences together, this variant is classified as Likely Pathogenic until additional reports demonstrating unequivocal co-segregation with disease in independent families with multiple affected and unaffected members are obtained. (less)
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Pathogenic
(Apr 04, 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: SCV000209237.13
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect as this variant alters troponin protein-protein interaction and calcium affinity (Mogensen et al., 2004; Mirza et al., 2005; … (more)
Published functional studies demonstrate a damaging effect as this variant alters troponin protein-protein interaction and calcium affinity (Mogensen et al., 2004; Mirza et al., 2005; Robinson et al., 2007; Liu et al., 2012; Gollapudi et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32458740, 17932326, 23302633, 24503780, 24817852, 28352236, 34935411, 21551322, 24119082, 15923195, 15542288, 20973921, 25163546, 18056765, 22337857, 27181684, 26183555, 25110706, 22464770, 27757084, 18506004, 27532257, 28611029, 31918855, 33025817, 32618513, 33906374, 22675533) (less)
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Likely 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: SCV004181413.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Likely 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: SCV004181414.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Likely 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: SCV004181412.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Likely pathogenic
(Jan 10, 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: SCV000736576.5
First in ClinVar: Apr 13, 2018 Last updated: Apr 15, 2023 |
Comment:
The p.R131W variant (also known as c.391C>T), located in coding exon 9 of the TNNT2 gene, results from a C to T substitution at nucleotide … (more)
The p.R131W variant (also known as c.391C>T), located in coding exon 9 of the TNNT2 gene, results from a C to T substitution at nucleotide position 391. The arginine at codon 131 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been previously reported in individuals with dilated cardiomyopathy (DCM) and left ventricular non-compaction (LVNC), and was reported as occurring de novo in a proband with LVNC and LV dilation (Mogensen J et al. J Am Coll Cardiol. 2004;44(10):2033-40; Klaassen S et al. Circulation. 2008;117(22):2893-901 (reported as c.450C>T); Pugh TJ et al. Genet Med. 2014;16(8):601-8). One study identified this variant in a family with a DCM/LVNC complex phenotype, where it was reportedly absent in the proband's affected parent, though clinical details were limited (Merlo M et al. Clin Transl Sci. 2013;6(6):424-8). Functional studies suggest this variant to result in impaired protein interaction and altered calcium binding properties (Mogensen et al. 2004; Mirza M et al. J Biol Chem. 2005; 280(31):28498-506; Robinson P et al. Circ Res. 2007;101(12):1266-73). This variant 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)
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Pathogenic
(Mar 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: SCV000541919.8
First in ClinVar: May 29, 2016 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 131 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 131 of the TNNT2 protein (p.Arg131Trp). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 15542288, 15923195, 17932326, 22675533). 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. ClinVar contains an entry for this variant (Variation ID: 12415). This missense change has been observed in individual(s) with dilated cardiomyopathy (DCM) and left ventricular non compaction (LVNC) (PMID: 15542288, 18506004, 21551322, 24119082). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). (less)
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Pathogenic
(Jun 03, 2008)
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no assertion criteria provided
Method: literature only
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CARDIOMYOPATHY, DILATED, 1D
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033473.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
Dilated Cardiomyopathy 1D In a 28-year-old woman with dilated cardiomyopathy (CMD1D; 601494), Mogensen et al. (2004) identified heterozygosity for an arg131-to-trp (R131W) substitution at a … (more)
Dilated Cardiomyopathy 1D In a 28-year-old woman with dilated cardiomyopathy (CMD1D; 601494), Mogensen et al. (2004) identified heterozygosity for an arg131-to-trp (R131W) substitution at a conserved residue in exon 10 of the TNNT2 gene. An older brother had died suddenly at 16 years of age; their mother had CMD and died of heart failure at 34 years of age. The mutation was not found in her unaffected older brother or father, or in 200 ethnically matched control chromosomes. Functional studies showed significant impairment of mutated troponin interaction compared with wildtype control, indicating an altered regulation of myocardial contractility. Left Ventricular Noncompaction 6 In a 20-year-old woman who presented in cardiogenic shock and was diagnosed with isolated left ventricular noncompaction (LVNC6; see 601494), Klaassen et al. (2008) identified heterozygosity for the R131W mutation in TNNT2. The patient had primarily midlateral and midinferior LVNC, left ventricular dilation, and impaired left ventricular systolic function. The de novo mutation was not present in her unaffected parents, and was not found in 360 control chromosomes. Variant Function Mirza et al. (2005) studied the R131W mutation and found that thin filaments reconstituted with a 1:1 ratio of mutant:wildtype proteins showed reduced Ca(2+) sensitivity of activation in ATPase and motility assays and a lower maximum Ca(2+) activation. (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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Dilated cardiomyopathy mutations in thin-filament regulatory proteins reduce contractility, suppress systolic Ca(2+), and activate NFAT and Akt signaling. | Robinson P | American journal of physiology. Heart and circulatory physiology | 2020 | PMID: 32618513 |
Insights and Challenges of Multi-Scale Modeling of Sarcomere Mechanics in cTn and Tm DCM Mutants-Genotype to Cellular Phenotype. | Dewan S | Frontiers in physiology | 2017 | PMID: 28352236 |
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 |
Dilated Cardiomyopathy Mutation (R134W) in Mouse Cardiac Troponin T Induces Greater Contractile Deficits against α-Myosin Heavy Chain than against β-Myosin Heavy Chain. | Gollapudi SK | Frontiers in physiology | 2016 | PMID: 27757084 |
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 |
Poor prognosis of rare sarcomeric gene variants in patients with dilated cardiomyopathy. | Merlo M | Clinical and translational science | 2013 | PMID: 24119082 |
Disease-related cardiac troponins alter thin filament Ca2+ association and dissociation rates. | Liu B | PloS one | 2012 | PMID: 22675533 |
Sarcomere gene mutations in isolated left ventricular noncompaction cardiomyopathy do not predict clinical phenotype. | Probst S | Circulation. Cardiovascular genetics | 2011 | PMID: 21551322 |
How do mutations in contractile proteins cause the primary familial cardiomyopathies? | Marston SB | Journal of cardiovascular translational research | 2011 | PMID: 21424860 |
Thin filament mutations: developing an integrative approach to a complex disorder. | Tardiff JC | Circulation research | 2011 | PMID: 21415410 |
Late onset sporadic dilated cardiomyopathy caused by a cardiac troponin T mutation. | Morales A | Clinical and translational science | 2010 | PMID: 20973921 |
Malignant and benign mutations in familial cardiomyopathies: insights into mutations linked to complex cardiovascular phenotypes. | Xu Q | Journal of molecular and cellular cardiology | 2010 | PMID: 20298698 |
Severe familial left ventricular non-compaction cardiomyopathy due to a novel troponin T (TNNT2) mutation. | Luedde M | Cardiovascular research | 2010 | PMID: 20083571 |
The changes of the cardiac structure and function in cTnTR141W transgenic mice. | Juan F | International journal of cardiology | 2008 | PMID: 18606313 |
Mutations in sarcomere protein genes in left ventricular noncompaction. | Klaassen S | Circulation | 2008 | PMID: 18506004 |
Troponin: regulatory function and disorders. | Ohtsuki I | Biochemical and biophysical research communications | 2008 | PMID: 18154728 |
Sarcomeric proteins and inherited cardiomyopathies. | Morimoto S | Cardiovascular research | 2008 | PMID: 18056765 |
Dilated and hypertrophic cardiomyopathy mutations in troponin and alpha-tropomyosin have opposing effects on the calcium affinity of cardiac thin filaments. | Robinson P | Circulation research | 2007 | PMID: 17932326 |
Molecular pathogenic mechanisms of cardiomyopathies caused by mutations in cardiac troponin T. | Morimoto S | Advances in experimental medicine and biology | 2007 | PMID: 17278368 |
The miscommunicative cardiac cell: when good proteins go bad. | Gomes AV | Annals of the New York Academy of Sciences | 2005 | PMID: 16093482 |
Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype. | Mirza M | The Journal of biological chemistry | 2005 | PMID: 15923195 |
Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy. | Mogensen J | Journal of the American College of Cardiology | 2004 | PMID: 15542288 |
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Text-mined citations for rs74315380 ...
HelpRecord last updated Mar 05, 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.