ClinVar Genomic variation as it relates to human health
NM_000363.5(TNNI3):c.470C>T (p.Ala157Val)
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_000363.5(TNNI3):c.470C>T (p.Ala157Val)
Variation ID: 43388 Accession: VCV000043388.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.42 19: 55154109 (GRCh38) [ NCBI UCSC ] 19: 55665477 (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 1, 2016 Feb 28, 2024 Nov 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000363.5:c.470C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000354.4:p.Ala157Val missense NC_000019.10:g.55154109G>A NC_000019.9:g.55665477G>A NG_007866.2:g.8624C>T NG_011829.2:g.130C>T LRG_432:g.8624C>T LRG_432t1:c.470C>T LRG_679:g.130C>T P19429:p.Ala157Val - Protein change
- A157V
- Other names
- p.A157V:GCG>GTG
- Canonical SPDI
- NC_000019.10:55154108: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.
Trans-Omics for Precision Medicine (TOPMed) 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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TNNI3 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
663 | 726 |
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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Pathogenic (4) |
criteria provided, single submitter
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Aug 3, 2023 | RCV000159227.13 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2023 | RCV000465603.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 8, 2017 | RCV000578464.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 6, 2020 | RCV001174966.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 14, 2022 | RCV001170616.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 4, 2023 | RCV002336121.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 6, 2023 | RCV003415768.4 |
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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Pathogenic
(Aug 03, 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: SCV000209173.17
First in ClinVar: Feb 24, 2015 Last updated: Aug 13, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22857948, 26199943, 27532257, 19645627, 21533915, 26506446, 21310275, 25524337, 28166811, 24111713, 25351510, 16335287, 24704860, 23283745, 25239116, 15607392, 12707239, 28971120, 35288587, 34076677, 35653365, 28193612) (less)
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Pathogenic
(Apr 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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TNNI3-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004106660.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The TNNI3 c.470C>T variant is predicted to result in the amino acid substitution p.Ala157Val. This variant has been reported in multiple individuals with dilated or … (more)
The TNNI3 c.470C>T variant is predicted to result in the amino acid substitution p.Ala157Val. This variant has been reported in multiple individuals with dilated or hypertrophic cardiomyopathy (see for example - Richard et al. 2003. PubMed ID: 12707239; Table SI - Captur et al. 2014. PubMed ID: 24704860; Table S1A/B - Walsh et al. 2016. PubMed ID: 27532257). Functional studies (Zheng et al. 2015. PubMed ID: 26506446). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been interpreted by multiple labs to be likely pathogenic/pathogenic in ClinVar (https://ncbi.nlm.nih.gov/clinvar/variation/43388/). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Nov 14, 2022)
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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: SCV004359898.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces alanine with valine at codon 157 in the C-terminal mobile domain of the TNNI3 protein. Computational prediction is inconclusive regarding the … (more)
This missense variant replaces alanine with valine at codon 157 in the C-terminal mobile domain of the TNNI3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 20 individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 15607392, 19645627, 21533915, 22386593, 22857948, 25524337, 26506446, 27532257, 15607392, 26506446). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 27532257). It has been shown that this variant segregates with disease in at least 7 individuals affected with hypertrophic cardiomyopathy across 4 families (PMID: 15607392, 26506446). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Nov 08, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 7
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München
Accession: SCV000680411.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
Sex: male
Tissue: blood
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Pathogenic
(Apr 06, 2020)
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criteria provided, single submitter
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001338448.1
First in ClinVar: Jun 18, 2020 Last updated: Jun 18, 2020 |
Comment:
Variant summary: TNNI3 c.470C>T (p.Ala157Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: TNNI3 c.470C>T (p.Ala157Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249082 control chromosomes (gnomAD). c.470C>T has been reported in the literature in several individuals affected with Hypertrophic Cardiomyopathy (Richard_2003, Brito_2005, Mogensen_2004, Curila_2009, Zheng_2016, Walsh_2017), and in many families the variant was demonstrated to segregate with the disease, (Richard_2003, Mogensen_2004, Curila_2009, Zheng_2016). The phenotypic manifestations ranged from clinically silent to sudden cardiac death, in addition the variant was also reported in an individual with dilated cardiomyopathy (Walsh_2017); these reports might indicate a variable penetrance. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant resulted in a decreased level of the TNNI3 protein in a mammalian cell based expression system (Zheng_2016). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 05, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059951.7
First in ClinVar: May 03, 2013 Last updated: May 29, 2021 |
Comment:
The p.Ala157Val variant in TNNI3 has been reported in > 20 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in at least 7 affected … (more)
The p.Ala157Val variant in TNNI3 has been reported in > 20 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in at least 7 affected individuals from at least 6 families (Richard 2003 PMID: 12707239; Mogensen 2004 PMID: 15607392; Brito 2005 PMID: 16335287, Curila 2009 PMID: 19645627; van den Wijngaard 2011 PMID: 21533915; Coppini 2014 PMID: 25524337; Walsh 2017 PMID: 27532257; LMM internal data). This variant has also been reported in 2 individuals with sudden death at a young age (van den Wijngaard 2011 PMID: 21533915) and in one individual with DCM (Walsh 2017 PMID: 27532257). Additionally, the p.Ala157Val variant has been reported by other clinical laboratories in ClinVar (Variation ID: 43388) and was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_Supporting. (less)
Number of individuals with the variant: 36
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Pathogenic
(Aug 23, 2019)
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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: SCV001333205.2
First in ClinVar: May 31, 2020 Last updated: Dec 29, 2021 |
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Likely pathogenic
(May 04, 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: SCV002637630.2
First in ClinVar: Nov 29, 2022 Last updated: Jul 08, 2023 |
Comment:
The p.A157V variant (also known as c.470C>T), located in coding exon 7 of the TNNI3 gene, results from a C to T substitution at nucleotide … (more)
The p.A157V variant (also known as c.470C>T), located in coding exon 7 of the TNNI3 gene, results from a C to T substitution at nucleotide position 470. The alanine at codon 157 is replaced by valine, an amino acid with similar properties. This variant has been previously reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) and has also been reported to segregate with HCM in families; however, in some cases clinical details or genes analyzed were limited (Richard P et al. Circulation. 2003;107:2227-32; Mogensen J et al. J Am Coll Cardiol. 2004;44:2315-25; Brito D et al. Rev Port Cardiol. 2005;24:1137-46; Curila K et al. Genet Test Mol Biomarkers. 2009;13:647-50; van den Wijngaard A et al. Neth Heart J. 2011;19(7-8):344-51; Zou Y et al. Mol Biol Rep. 2013;40(6):3969-76; Berge KE et al. Clin Genet. 2014;86(4):355-60; Captur G. Circ Cardiovasc Genet. 2014;7(3):241-8; Coppini R et al. J Am Coll Cardiol. 2014;64(24):2589-600; Lopes LR et al. Heart. 2015;101:294-301). In vitro analysis from one study suggested a possible impact to protein expression as a result of this variant (Zheng H et al. Cardiology. 2016;133:91-6). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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
(Nov 27, 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: SCV000551893.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 157 of the TNNI3 protein (p.Ala157Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 157 of the TNNI3 protein (p.Ala157Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (PMID: 12707239, 15607392, 16335287, 19645627, 21533915, 23283745, 24111713, 24704860, 25239116, 25524337, 26506446, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43388). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001959911.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001922704.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001969854.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 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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Prevalence and Clinical Implication of Double Mutations in Hypertrophic Cardiomyopathy: Revisiting the Gene-Dose Effect. | Fourey D | Circulation. Cardiovascular genetics | 2017 | PMID: 28420666 |
Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients. | Gómez J | Circulation. Cardiovascular genetics | 2017 | PMID: 28356264 |
Lack of Phenotypic Differences by Cardiovascular Magnetic Resonance Imaging in MYH7 (β-Myosin Heavy Chain)- Versus MYBPC3 (Myosin-Binding Protein C)-Related Hypertrophic Cardiomyopathy. | Weissler-Snir A | Circulation. Cardiovascular imaging | 2017 | PMID: 28193612 |
Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation. | Kobayashi Y | Genome medicine | 2017 | PMID: 28166811 |
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 |
A Double Heterozygous Mutation of TNNI3 Causes Hypertrophic Cardiomyopathy in a Han Chinese Family. | Zheng H | Cardiology | 2016 | PMID: 26506446 |
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations. | Coppini R | Journal of the American College of Cardiology | 2014 | PMID: 25524337 |
Advanced heart failure with preserved systolic function in nonobstructive hypertrophic cardiomyopathy: under-recognized subset of candidates for heart transplant. | Rowin EJ | Circulation. Heart failure | 2014 | PMID: 25239116 |
Abnormal cardiac formation in hypertrophic cardiomyopathy: fractal analysis of trabeculae and preclinical gene expression. | Captur G | Circulation. Cardiovascular genetics | 2014 | PMID: 24704860 |
Genetics of hypertrophic cardiomyopathy in Norway. | Berge KE | Clinical genetics | 2014 | PMID: 24111713 |
Multiple gene mutations, not the type of mutation, are the modifier of left ventricle hypertrophy in patients with hypertrophic cardiomyopathy. | Zou Y | Molecular biology reports | 2013 | PMID: 23283745 |
Sarcomeric hypertrophic cardiomyopathy: genetic profile in a Portuguese population. | Brito D | Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology | 2012 | PMID: 22857948 |
PGD for inherited cardiac diseases. | Kuliev A | Reproductive biomedicine online | 2012 | PMID: 22386593 |
Recurrent and founder mutations in the Netherlands: cardiac Troponin I (TNNI3) gene mutations as a cause of severe forms of hypertrophic and restrictive cardiomyopathy. | van den Wijngaard A | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2011 | PMID: 21533915 |
Development and validation of a computational method for assessment of missense variants in hypertrophic cardiomyopathy. | Jordan DM | American journal of human genetics | 2011 | PMID: 21310275 |
Low prevalence and variable clinical presentation of troponin I and troponin T gene mutations in hypertrophic cardiomyopathy. | Curila K | Genetic testing and molecular biomarkers | 2009 | PMID: 19645627 |
Malignant mutations in hypertrophic cardiomyopathy: fact or fancy? | Brito D | Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology | 2005 | PMID: 16335287 |
Inherited cardiomyopathies as a troponin disease. | Harada K | The Japanese journal of physiology | 2004 | PMID: 15631686 |
Frequency and clinical expression of cardiac troponin I mutations in 748 consecutive families with hypertrophic cardiomyopathy. | Mogensen J | Journal of the American College of Cardiology | 2004 | PMID: 15607392 |
Cellular and molecular aspects of familial hypertrophic cardiomyopathy caused by mutations in the cardiac troponin I gene. | Gomes AV | Molecular and cellular biochemistry | 2004 | PMID: 15524171 |
Molecular and cellular aspects of troponin cardiomyopathies. | Gomes AV | Annals of the New York Academy of Sciences | 2004 | PMID: 15201162 |
Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. | Richard P | Circulation | 2003 | PMID: 12707239 |
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Text-mined citations for rs397516353 ...
HelpRecord last updated Mar 11, 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.