ClinVar Genomic variation as it relates to human health
NM_000363.5(TNNI3):c.204del (p.Arg69fs)
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(4); Likely pathogenic(2); Uncertain significance(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000363.5(TNNI3):c.204del (p.Arg69fs)
Variation ID: 179447 Accession: VCV000179447.25
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 19q13.42 19: 55156279 (GRCh38) [ NCBI UCSC ] 19: 55667647 (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 Jun 3, 2016 Feb 20, 2024 Nov 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000363.5:c.204del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000354.4:p.Arg69fs frameshift NM_000363.5:c.204delG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000363.4:c.204del NC_000019.10:g.55156280del NC_000019.9:g.55667648del NG_007866.2:g.6454del LRG_432:g.6454del LRG_432t1:c.204del - Protein change
- R69fs
- Other names
- p..R69AfsX8
- Canonical SPDI
- NC_000019.10:55156278:CC:C
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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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TNNI3 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
- | 723 |
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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Aug 15, 2017 | RCV000159255.9 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 11, 2023 | RCV000223861.8 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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May 18, 2023 | RCV001526043.4 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV002056120.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 8, 2022 | RCV002281968.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 14, 2023 | RCV002415672.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 17, 2023 | RCV001237455.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 20, 2019 | RCV001254648.1 |
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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Uncertain significance
(Aug 15, 2017)
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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: SCV000205952.5
First in ClinVar: Jan 31, 2015 Last updated: Apr 17, 2019 |
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg69fs v ariant in TNNI3 has been observed in our laboratory in one homozygous individual with … (more)
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg69fs v ariant in TNNI3 has been observed in our laboratory in one homozygous individual with neonatal onset HCM/DCM. It has been identified in 5/33086 Latino chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/ ; dbSNP rs727504872). This variant has been reported in ClinVar variation ID 179 447. This frameshift variant is predicted to alter the protein?s amino acid sequ ence beginning at position 69 and lead to a premature termination codon 8 amino acids downstream. This alteration is then predicted to lead to a truncated or ab sent protein. Although this variant is predicted to be deleterious to the protei n, the variant spectrum of this gene has not been well characterized, and it rem ains unclear if these variant types play a role in disease. In summary, while th ere is some suspicion for a pathogenic role, the clinical significance of the p. Arg69fs variant is uncertain. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 20, 2019)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 2A
Affected status: yes
Allele origin:
germline
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Hadassah Hebrew University Medical Center
Accession: SCV001430680.1
First in ClinVar: Aug 23, 2020 Last updated: Aug 23, 2020 |
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447351.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Primary dilated cardiomyopathy (present)
Sex: male
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Pathogenic
(-)
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criteria provided, single submitter
Method: research
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Myocarditis
Primary dilated cardiomyopathy
Affected status: yes
Allele origin:
germline
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Klaassen Lab, Charite University Medicine Berlin
Accession: SCV002495744.1
First in ClinVar: Apr 08, 2022 Last updated: Apr 08, 2022 |
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Likely pathogenic
(Mar 24, 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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502922.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Likely pathogenic
(Aug 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Primary familial dilated cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002571861.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: TNNI3 c.204delG (p.Arg69AlafsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: TNNI3 c.204delG (p.Arg69AlafsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. The variant allele was found at a frequency of 3.8e-05 in 236002 control chromosomes (gnomAD). c.204delG has been reported in the literature in multiple homozygous individuals affected with Dilated Cardiomyopathy who had inherited the variant from their unaffected heterozygous parents (e.g. Kuhnisch_2019, Pezzoli_2021, Seidel_2021). TNNI3 protein was absent and mRNA level was markedly reduced in heart biopsies from some of these homozygous patients (Kuhnisch_2019, Pezzoli_2021). Even though loss-of-function (LoF) has not been established as a molecular mechanism of disease for TNNI3 gene, accumulated evidence suggests that LoF variants can be causative for autosomal recessive Dilated Cardiomyopathy. These data indicate that the variant is likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and four ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Some submitters cite overlapping but not identical evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Uncertain significance
(Jan 11, 2023)
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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: SCV000209201.14
First in ClinVar: Feb 24, 2015 Last updated: Mar 11, 2023 |
Comment:
Reported in association with cardiomyopathy or arrhythmia, without patient-specific clinical data (Chanavat et al. 2016); Frameshift variant predicted to result in protein truncation or nonsense … (more)
Reported in association with cardiomyopathy or arrhythmia, without patient-specific clinical data (Chanavat et al. 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; Reported in ClinVar with conflicting classifications and has been reported by a clinical laboratory in one homozygous individual with neonatal onset HCM/DCM (ClinVar Variant ID# 179447; SCV000205952.5); This variant is associated with the following publications: (PMID: 26688388, 31568572, 34213952, 35050212) (less)
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Uncertain significance
(Feb 14, 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: SCV002726529.2
First in ClinVar: Nov 29, 2022 Last updated: Apr 15, 2023 |
Comment:
The c.204delG variant, located in coding exon 5 of the TNNI3 gene, results from a deletion of one nucleotide at nucleotide position 204, causing a … (more)
The c.204delG variant, located in coding exon 5 of the TNNI3 gene, results from a deletion of one nucleotide at nucleotide position 204, causing a translational frameshift with a predicted alternate stop codon (p.R69Afs*8). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of TNNI3 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(May 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV004239768.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Uncertain significance
(May 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001736312.2
First in ClinVar: Jun 19, 2021 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 1 nucleotide in exon 5 of the TNNI3 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 1 nucleotide in exon 5 of the TNNI3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. An experimental functional study using heart tissue from a homozygous individual affected with dilated cardiomyopathy has shown that TNNI3 protein was not expressed in heart tissue (PMID: 31568572). This variant has been reported in homozygosity in multiple individuals affected with early-onset dilated cardiomyopathy (PMID: 31568572, 35050212, 36981019); heterozygous carrier parents were either not clinically affected or were not fully clinically evaluated for TNNI3-related disorders. This variant has also been reported in heterozygosity in an individual affected with dilated cardiomyopathy (PMID: 36129056), in unclear zygosity in another individual affected with dilated cardiomyopathy (PMID: 34286374), and in an individual affected with cardiomyopathy or arrhythmia (PMID: 26688388). This variant has been identified in 9/236002 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function TNNI3 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Pathogenic
(Nov 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001410216.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg69Alafs*8) in the TNNI3 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg69Alafs*8) in the TNNI3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TNNI3 are known to be pathogenic (PMID: 31568572, 34036930, 35838873). This variant is present in population databases (rs727504872, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive dilated cardiomyopathy (PMID: 31568572). ClinVar contains an entry for this variant (Variation ID: 179447). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Nov 13, 2013)
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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: SCV000280497.1
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 (less)
Number of individuals with the variant: 1
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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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Homozygous TNNI3 Mutations and Severe Early Onset Dilated Cardiomyopathy: Patient Report and Review of the Literature. | Sorrentino U | Genes | 2023 | PMID: 36981019 |
Determining the Likelihood of Disease Pathogenicity Among Incidentally Identified Genetic Variants in Rare Dilated Cardiomyopathy-Associated Genes. | Yang Q | Journal of the American Heart Association | 2022 | PMID: 36129056 |
Molecular Diagnosis of Primary Cardiomyopathy in 231 Unrelated Pediatric Cases by Panel-Based Next-Generation Sequencing: A Major Focus on Five Carriers of Biallelic TNNI3 Pathogenic Variants. | Janin A | Molecular diagnosis & therapy | 2022 | PMID: 35838873 |
Differences between genetic dilated cardiomyopathy and myocarditis in children presenting with severe cardiac dysfunction. | Gran F | European journal of pediatrics | 2022 | PMID: 34286374 |
Molecular analysis of dilated and left ventricular noncompaction cardiomyopathies in Egyptian children. | Mehaney DA | Cardiology in the young | 2022 | PMID: 34036930 |
Not Only Diagnostic Yield: Whole-Exome Sequencing in Infantile Cardiomyopathies Impacts on Clinical and Family Management. | Pezzoli L | Journal of cardiovascular development and disease | 2021 | PMID: 35050212 |
Pathogenic Variants Associated With Dilated Cardiomyopathy Predict Outcome in Pediatric Myocarditis. | Seidel F | Circulation. Genomic and precision medicine | 2021 | PMID: 34213952 |
Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3. | Kühnisch J | Clinical genetics | 2019 | PMID: 31568572 |
A fast and cost-effective molecular diagnostic tool for genetic diseases involved in sudden cardiac death. | Chanavat V | Clinica chimica acta; international journal of clinical chemistry | 2016 | PMID: 26688388 |
Defective dynamic properties of human cardiac troponin mutations. | Lassalle MW | Bioscience, biotechnology, and biochemistry | 2010 | PMID: 20057144 |
Deletion in TNNI3 gene is associated with restrictive cardiomyopathy. | Kostareva A | International journal of cardiology | 2009 | PMID: 18006163 |
Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. | Olivotto I | Mayo Clinic proceedings | 2008 | PMID: 18533079 |
Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes. | Kaski JP | Heart (British Cardiac Society) | 2008 | PMID: 18467357 |
Functional consequences of the mutations in human cardiac troponin I gene found in familial hypertrophic cardiomyopathy. | Takahashi-Yanaga F | Journal of molecular and cellular cardiology | 2001 | PMID: 11735257 |
Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. | Kimura A | Nature genetics | 1997 | PMID: 9241277 |
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Text-mined citations for rs727504872 ...
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.