ClinVar Genomic variation as it relates to human health
NM_001276345.2(TNNT2):c.548G>A (p.Arg183Gln)
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.548G>A (p.Arg183Gln)
Variation ID: 43649 Accession: VCV000043649.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q32.1 1: 201363348 (GRCh38) [ NCBI UCSC ] 1: 201332476 (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 Dec 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001276345.2:c.548G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001263274.1:p.Arg183Gln missense NM_000364.4:c.548G>A NP_000355.2:p.Arg183Gln missense NM_001001430.3:c.518G>A NP_001001430.1:p.Arg173Gln missense NM_001001431.3:c.518G>A NP_001001431.1:p.Arg173Gln missense NM_001001432.3:c.503G>A NP_001001432.1:p.Arg168Gln missense NM_001276346.2:c.428G>A NP_001263275.1:p.Arg143Gln missense NM_001276347.2:c.518G>A NP_001263276.1:p.Arg173Gln missense NC_000001.11:g.201363348C>T NC_000001.10:g.201332476C>T NG_007556.1:g.19330G>A LRG_431:g.19330G>A LRG_431t1:c.548G>A LRG_431p1:p.Arg183Gln - Protein change
- R173Q, R183Q, R143Q, R168Q
- Other names
- p.R173Q:CGG>CAG
- Canonical SPDI
- NC_000001.11:201363347: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
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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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TNNT2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
898 | 917 |
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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Likely pathogenic (1) |
criteria provided, single submitter
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Oct 10, 2018 | RCV000036597.6 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 8, 2021 | RCV000159340.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 28, 2023 | RCV000233887.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 19, 2018 | RCV002336123.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003450709.1 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Apr 11, 2023 | RCV001594378.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003450708.1 |
Submissions - Germline
Classification
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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
(Jun 05, 2017)
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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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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000747940.1
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016 |
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Pathogenic
(Dec 08, 2021)
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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: SCV000209286.13
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 43649; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 22464770, 25163546, 19324435, 28588840, 28669108, 29367539, 33019804) (less)
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Likely pathogenic
(Oct 10, 2018)
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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: SCV000060252.6
First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019 |
Comment:
The p.Arg173Gln variant in TNNT2 has been identified 3 individuals with DCM (1 w ith infantile onset and 1 with prenatal onset ) and segregated … (more)
The p.Arg173Gln variant in TNNT2 has been identified 3 individuals with DCM (1 w ith infantile onset and 1 with prenatal onset ) and segregated with disease in 6 affected relatives with varying ages of onset from 2 families (Van Acker 2009, Ferlund 2017, LMM data). It was absent from large population studies. Computatio nal prediction tools and conservation analysis are consistent with pathogenicity . Two additional variants involving this codon (p.Arg173Gly and p.Arg173Trp) hav e been identified in individuals with DCM, and p.Arg173Trp is classified as path ogenic by this laboratory. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM. ACMG/AMP criteria ap plied: PM2, PM5, PP1_Moderate, PP3, PS4_Supporting. (less)
Number of individuals with the variant: 3
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Pathogenic
(Sep 19, 2018)
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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: SCV002644166.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R173Q pathogenic mutation (also known as c.518G>A), located in coding exon 10 of the TNNT2 gene, results from a G to A substitution at … (more)
The p.R173Q pathogenic mutation (also known as c.518G>A), located in coding exon 10 of the TNNT2 gene, results from a G to A substitution at nucleotide position 518. The arginine at codon 173 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in multiple probands with dilated cardiomyopathy (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; Fernlund E et al. Pediatr Cardiol, 2017 Aug;38:1262-1268). In addition, another alteration affecting the same amino acid, p.R173W (c.517C>T), has been reported in association with DCM (Sun N et al. Sci Transl Med, 2012 Apr;4:130ra47). 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
(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: SCV004181316.1
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: SCV004181317.1
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: SCV004181315.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Dec 28, 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: SCV000285653.8
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 173 of the TNNT2 protein (p.Arg173Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 173 of the TNNT2 protein (p.Arg173Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 19324435, 22464770, 28669108). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43649). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg173 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24119082). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Dec 29, 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: SCV000280528.1
First in ClinVar: May 29, 2016 Last updated: May 29, 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.Arg173Gln has been previously associated with DCM—and shown to segregate with disease in five affected members of the same family, including one sudden cardiac death. It has also been reported in another, unrelated case of sudden cardiac death. Van Acker et al. (2009) reported this variant to co-segregate with disease in five individuals from three generations of a family affected by DCM. The family’s race is not mentioned, but the researchers were located in Belgium. The proband had prenatal-onset disease (identified by fetal echocardiogram), and her brother also had DCM as a newborn; they and three other clinically affected relatives carried the Arg173Gln variant. This includes the proband’s mother and maternal uncle (the uncle’s affected son was not tested for the variant). It also includes the maternal grandmother, who had died suddenly of “arrhythmia” at the age of 47 and could not be tested, but her husband tested negative for the variant. The proband’s sister, the only unaffected mutation carrier, remained asymptomatic and had normal findings on echocardiography at the age of 21 years. In addition, Hernandez Del Rincon et al. (2011) reported in a poster session that they found this variant in a case of sudden cardiac death in Spain (19th International Association of Forensic Sciences World Meeting). The brief poster abstract does not contain additional phenotype data for the deceased, such as whether DCM was detected, although it mentions that a complete autopsy was performed. Variation at this and nearby loci of TNNT2 has been associated with disease. Arg173Trp (another variant at this same codon) has been seen in at least 3 unrelated individuals with cardiomyopathy and shown to segregate with disease in 4 members of a SCICD family with DCM (please see that variant analysis). Ala172Ser has been reported as a pathogenic mutation causing DCM; Glu163Lys, Glu163Arg, and Ser179Phe have been reported as pathogenic mutations causing HCM (Willott et al. 2010; Harvard Sarcomere Protein Gene Mutation Database). This is a chemically semi-conservative amino acid change: The variant substitutes a positively-charged amino acid (Arginine) with a polar, uncharged amino acid (Glutamine). The Arginine at position 173 is highly conserved across vertebrate evolution, although in zebrafish and medaka fish it is instead a positively-charged Lysine and in lamprey a Methionine. In silico analysis (PolyPhen-2) predicts the Arg173Gln variant to be “probably damaging.” Van Acker et al. (2009) did not observe the variant in 100 presumably healthy control individuals. Their race is not mentioned, but the study was conducted in Belgium. The variant was not seen in 3509 Caucasian individuals in NHLBI’s Exome Variant Server, nor in 1869 African American individuals (http://evs.gs.washington.edu/EVS/). The phenotype of these individuals is not publicly available, however the cohort has been screened to exclude those with evidence of Mendelian cardiac disease. The variant is not reported in 1000 Genomes (http://browser.1000genomes.org/index.html) (as of December 29, 2011). This contains 70 individuals of Colombian ancestry as well as over 400 Europeans. The patient’s father’s side of the family is Colombian and her mother’s side of the family includes Northern European Caucasian as well as Native American ancestry. The extensive Caucasian control data is most applicable, therefore, if her mother’s side of the family is the one affected. Assessment: Given the strong segregation data for this variant (albeit in only one family), the likely relevance of the Caucasian control data to that family, and two independent reports of sudden cardiac death associated with the variant, we believe Arg173Gln in TNNT2 is likely to be disease causing. In addition, another variant at this same amino acid residue (Arg173Trp) has segregated with disease in 3 members of a SCICD family with DCM, bolstering the functional importance of this site in the protein. It is therefore appropriate to use for predictive genetic testing for family members. Once the patient’s parents and other family members have been phenotyped, we may be in a position to strengthen this conclusion with segregation data. It is worth considering that the severity and early onset of the patient’s disease could be suggestive of two variants, possibly one from each side of the family. (less)
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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Dilated cardiomyopathy 1D
Affected status: yes
Allele origin:
germline
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KTest Genetics, KTest
Accession: SCV001499978.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
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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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Multiple Species Comparison of Cardiac Troponin T and Dystrophin: Unravelling the DNA behind Dilated Cardiomyopathy. | England J | Journal of cardiovascular development and disease | 2017 | PMID: 29367539 |
Novel Genetic Variants in BAG3 and TNNT2 in a Swedish Family with a History of Dilated Cardiomyopathy and Sudden Cardiac Death. | Fernlund E | Pediatric cardiology | 2017 | PMID: 28669108 |
Additional coronary sinus shocking lead as rescue therapy after multiple internal and external defibrillation failures. | Chauveau S | Clinical case reports | 2017 | PMID: 28588840 |
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 |
Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy. | Sun N | Science translational medicine | 2012 | PMID: 22517884 |
Genetic testing for dilated cardiomyopathy in clinical practice. | Lakdawala NK | Journal of cardiac failure | 2012 | PMID: 22464770 |
Dilated cardiomyopathy caused by a novel TNNT2 mutation-added value of genetic testing in the correct identification of affected subjects. | Van Acker H | International journal of cardiology | 2010 | PMID: 19324435 |
Text-mined citations for rs397516471 ...
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.