ClinVar Genomic variation as it relates to human health
NM_000363.5(TNNI3):c.433C>T (p.Arg145Trp)
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.433C>T (p.Arg145Trp)
Variation ID: 12426 Accession: VCV000012426.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.42 19: 55154146 (GRCh38) [ NCBI UCSC ] 19: 55665514 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 29, 2016 Oct 8, 2024 Jan 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000363.5:c.433C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000354.4:p.Arg145Trp missense NC_000019.10:g.55154146G>A NC_000019.9:g.55665514G>A NG_007866.2:g.8587C>T NG_011829.2:g.93C>T LRG_432:g.8587C>T LRG_432t1:c.433C>T LRG_679:g.93C>T P19429:p.Arg145Trp - Protein change
- R145W
- Other names
- p.R145W:CGG>TGG
- Canonical SPDI
- NC_000019.10:55154145: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 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
Help
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 |
699 | 760 |
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 (1) |
no assertion criteria provided
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Jan 1, 2003 | RCV000013239.23 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Dec 15, 2022 | RCV000159222.17 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 21, 2024 | RCV000498333.18 | |
Pathogenic (1) |
no assertion criteria provided
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Jan 21, 2019 | RCV001254730.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 7, 2023 | RCV001170617.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 1, 2021 | RCV001787387.1 | |
TNNI3-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Feb 27, 2024 | RCV004549357.2 |
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
(Feb 09, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, University of Leuven
Accession: SCV000579511.1
First in ClinVar: Aug 20, 2017 Last updated: Aug 20, 2017 |
Comment:
ACMG score pathogenic
Number of individuals with the variant: 9
Family history: yes
Age: 1-70 years
Sex: mixed
Ethnicity/Population group: Caucasian
Geographic origin: Belgium
Secondary finding: no
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Pathogenic
(Dec 15, 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: SCV000209168.14
First in ClinVar: Feb 24, 2015 Last updated: Dec 24, 2022 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect including increased Ca2+ sensitivity of both force development … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect including increased Ca2+ sensitivity of both force development and ATPase activity (Gomes et al. 2005; Yumoto et al., 2005; Kobayashi et al., 2006; Wen et al. 2009; Parvatiyar et al., 2010); 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: 16020591, 18423659, 19651143, 27557662, 31513939, 23508784, 32492895, 15961398, 15992656, 16288990, 17599605, 18409188, 19035361, 19914256, 20617149, 23283745, 19289050, 28166811, 28382084, 28650931, 27766529, 28181243, 21310275, 25351510, 27532257, 12531876, 28790153, 29661763, 31308319, 33087929, 30847666, 31447099, 32480058, 33673806, 32686758, 24704860, 35027292, 16531415, 15607392, 21533915) (less)
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Pathogenic
(Jan 31, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000927140.1
First in ClinVar: Jul 24, 2019 Last updated: Jul 24, 2019
Comment:
Patient analyzed with Hypertrophic Cardiomyopathy (HCM) Panel
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Pathogenic
(Jun 28, 2019)
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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: SCV000059946.7
First in ClinVar: May 03, 2013 Last updated: Jul 03, 2020 |
Comment:
The p.Arg145Trp variant in TNNI3 has been reported in >25 individuals with HCM or RCM and segregated with disease in >15 affected family members (Yumoto … (more)
The p.Arg145Trp variant in TNNI3 has been reported in >25 individuals with HCM or RCM and segregated with disease in >15 affected family members (Yumoto 2005, Mogensen 2004, Andersen 2009, Cheng 2005, Fokstuen 2008, Mogensen 2003, van den Wijngaard 2011, Walsh 2017, Hwang 2017, van Velzen 2018, LMM data). It was shown to be a Dutch founder mutation (van den Wijngaard 2011).This variant has also been identified in 3/280226 chromosomes by gnomAD (http://gnomad.broadinstitute.org/) and reported in ClinVar (Variation ID #12426). Functional studies in muscle fibers from transgenic mice showed an increase in force generation (Wen 2009). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PS3_Moderate. (less)
Number of individuals with the variant: 11
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Pathogenic
(Oct 01, 2021)
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criteria provided, single submitter
Method: research
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SUDDEN INFANT DEATH SYNDROME
Affected status: yes
Allele origin:
germline
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Robert's Program, Boston Children's Hospital
Accession: SCV002030072.1
First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 |
Comment:
We classify this variant as pathogenic using the following ACMG/AMP criteria: PS3, PS1, PP1, PP5
Clinical Features:
Sudden infant death syndrome (present)
Sex: female
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Pathogenic
(May 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767697.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene and both mechanisms have been functionally proven with missense variants (PMID: 21533915). (N) 0108 - This gene is known to be associated most commonly with dominant disease, however there is low evidence of association with recessive disease (OMIM). (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 15607392). (N) 0200 - Variant is predicted to result in a missense amino acid change from an arginine to a tryptophan (exon 7). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (4 heterozygotes, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and is highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif, (troponin domain; PDB, NCBI). (N) 0702 – Comparable missense variants at the same residue (p.Arg145Gly, p.Arg145Gln) have strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (ClinVar, LOVD). (P) 0801 - Strong previous evidence of pathogenicity in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM) (ClinVar, LOVD, PMID: 28382084). (P) 0903 - Evidence for segregation with disease in a family with both HCM and RCM (PMID: 28382084). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Transgenic mice were shown to have increased ATPase activity and longer muscle contractions (PMID: 19651143). (P) 1208 – Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Pathogenic
(Mar 07, 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: SCV001333206.3
First in ClinVar: May 31, 2020 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 21, 2024)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000623782.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 145 of the TNNI3 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 145 of the TNNI3 protein (p.Arg145Trp). This variant is present in population databases (rs104894724, gnomAD 0.003%). This missense change has been observed in individuals with hypertrophic cardiomyopathy and restrictive cardiomyopathy (PMID: 12531876, 21533915, 23283745, 27532257). ClinVar contains an entry for this variant (Variation ID: 12426). 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. Experimental studies have shown that this missense change affects TNNI3 function (PMID: 16531415, 18423659, 19289050, 19651143, 27557662). This variant disrupts the p.Arg145 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9241277, 11735257, 15607392, 23283745, 24111713, 25132132). 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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Pathogenic
(Jul 07, 2023)
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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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All of Us Research Program, National Institutes of Health
Accession: SCV004822603.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
The c.433C>T (p.Arg145Trp) variant in the TNNI3 gene is located on the exon 7 of the TNNI3 gene and is predicted to replace arginine with … (more)
The c.433C>T (p.Arg145Trp) variant in the TNNI3 gene is located on the exon 7 of the TNNI3 gene and is predicted to replace arginine with tryptophan at codon 145 of the TNNI3 protein (p.Arg145Trp). This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM) (PMID: 12531876, 15607392, 15992656, 16288990, 18409188, 19035361, 21533915, 23283745, 27532257, 28382084, 29661763) and segregate with diseases (PMID: 15607392, 19035361, 21533915, 21839045). This variant is a founder mutation in the Dutch population (PMID: 21533915). Functional studies showed that this variant leads to increased calcium sensitivity of both force development and ATPase activity (PMID: 15961398, 16288990, 16531415, 18269819, 18423659, 19289050, 19651143, 27557662). Other missense variants affecting the same amino acid residue (Arg145Gly and Arg145Gln) have been reported to be pathogenic. Computational evidence supports a deleterious effect on the protein structure and function. This variant has been observed at a low frequency (3/280226) in the general population according to gnomAD. Therefore, the c.433C>T (p.Arg145Trp) variant in the TNNI3 gene is classified as pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jan 01, 2003)
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no assertion criteria provided
Method: literature only
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CARDIOMYOPATHY, FAMILIAL RESTRICTIVE, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033486.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 09, 2016 |
Comment on evidence:
In 2 unrelated individuals with typical features of restrictive cardiomyopathy (RCM1; 115210) diagnosed in their late fifties, Mogensen et al. (2003) identified a 799C-T transition … (more)
In 2 unrelated individuals with typical features of restrictive cardiomyopathy (RCM1; 115210) diagnosed in their late fifties, Mogensen et al. (2003) identified a 799C-T transition in the TNNI3 gene, resulting in an arg145-to-trp (R145W) substitution. The sequence required for inhibition of human cardiac troponin I actomyosin ATPase activity consists of 21 amino acid residues (137-148) (Perry, 1999). Haplotype analysis with respect to the TNNI3 locus on chromosome 19 did not suggest a common founder effect. (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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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001925473.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 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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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001929208.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 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: SCV001973662.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(Feb 27, 2024)
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no assertion criteria provided
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: SCV004796957.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The TNNI3 c.433C>T variant is predicted to result in the amino acid substitution p.Arg145Trp. This variant was reported in numerous individuals with restrictive cardiomyopathy or … (more)
The TNNI3 c.433C>T variant is predicted to result in the amino acid substitution p.Arg145Trp. This variant was reported in numerous individuals with restrictive cardiomyopathy or hypertrophic cardiomyopathy (Mogensen et al. 2003. PubMed ID: 12531876; van den Wijngaard et al. 2011. PubMed ID: 21533915; Table S1A, Walsh et al. 2017. PubMed ID: 27532257; Table S2, Bagnall et al. 2022. PubMed ID: 36252119). Functional studies supported that this variant impacts normal protein function (described as p.Arg146Trp, Mathur et al. 2009. PubMed ID: 19289050; Wen et al. 2009. PubMed ID: 19651143; Dvornikov et al. 2016. PubMed ID: 27557662). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. Different nucleotide substitutions affecting the same amino acid (p.Arg145Gly and p.Arg145Gln) have been reported in individuals with hypertrophic cardiomyopathy (Human Gene Mutation Database). Taken together, the c.433C>T (p.Arg145Trp) variant is interpreted as pathogenic. (less)
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Likely pathogenic
(Apr 08, 2014)
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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: SCV000280507.1
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.Arg145Trp (c.433 C>T) in the TNNI3 gene Cardiomyocyte contraction is dependent on local sarcomeric calcium levels, which is regulated by the small troponin complex (three subunits I, C and T). Troponin I binds to the thin filament of the sarcomere and prevent muscle contraction by inhibiting the actomyosin activity of the myosin heavy chain. This inhibitory effect is released by calcium binding to troponin C. Troponin I3 is exclusively expressed in cardiac muscle and plays a centaral role in modulating cardiac muscle contraction and relaxation in response to changes in intracellular calcium. The prevalence of mutation in TNNI3 is believed to be <5% in different types of cardiomyopathies, with most commonly in HCM. This variant is in exon 7. The majority of variants in TNNI3 have been reported in exons 7 and 8. The variant has been seen in at least 10 unrelated cases of HCM or RCM with no segregation data. The p.Arg145Trp variant has been reported previously in association with HCM and restrictive cardiomyopathy (RCM) and the testing lab reports it has also been reported in multiple unrelated individuals testing for HCM at their lab. Mogensen et al (2003) reported this variant in two individuals with restrictive cardiomyopathy. Haplotype did not suggest a common founder effect. These two patients had typical features of RCM diagnosed in their late fifties with symptoms of heart failure. No segregation data was available. Van den Wijngaard et al (2011) reported this variant in eight patients from a cohort of 1040 with cardiomyopathy. 6 of these patients has HCM, one had RCM and one did not have enough information to determine phenotype. No segregation data was indicated. Families carrying the p.Arg145Trp variant showed LVH and ECG typical for HCM. All available ECGs for this cohort showed abnormalities in the patients with this variant. Most patients with this variant showed LVH and clear clinical symptoms between the age of 40-50. In three families, cases of sudden death had occurred: in one family at age 41 (RCM) and in the second family at age 50 (HCM). In the third family two cases of SCD were reported, one at age 13 and one at 38, although the authors could not confirm the presence of this variant in the deceased. In this same family, the sister of the proband who carried the variant was unaffected at age 67. Another proband survived an out-of-hospital cardiac arrest. The authors sate that p.Arg145Trp is the most frequent TNNI3 mutation in the Netherlands (27% of TNNI3 variants). Van den Wijngaard and colleagues performed haplotype analysis and suggest this is a founder mutations in the Dutch population. It has been shown that the sequence required for inhibition of human cardiac troponin I actomyopsin ATPase activity consists of 21 amino acid residues from number 137 to 148 (Syskka H e al., 1976)/ In additional in vitro expression studies have investigated previous reported TNNI3 mutation associated with HCM. Similar findings were reported following analysis of transgenic mice expressing a Arg145Gly variant (James J., 200) Multiple functional studies have noted Arg145Trp is located in the region of the gene that is required for inhibition of human cardiac troponin I actomyosin ATPase activite and Arg145Trp showed a large increase in CA2+ sensitively of both force development, ATPase activity and other functional impairments (Gomes A et al, 2005; Wen Y et al., 2009). In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The arginine at codon 145 is mostly conserved across species, it is a lysine at that position in C-elegans and D-melanogaster, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (Arg145Gln; Arg145Gly) and nearby codons (Arg141Gln; Arg144Gln; Arg144Pro). In total the variant has not been seen in ~6,610 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 145 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 10/30/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 10/30/13). The variant was not observed in the following laboratory and published control samples: Mogensen reported absence of this variant in 200 chromosomes from Caucasian control individuals. Van den Wijngaard reported these variants were not present in 10 control individuals. (less)
Number of individuals with the variant: 10
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Pathogenic
(Jan 21, 2019)
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no assertion criteria provided
Method: research
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Hypertrophic cardiomyopathy
Restrictive cardiomyopathy (Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV001430810.1
First in ClinVar: Aug 23, 2020 Last updated: Aug 23, 2020 |
Comment:
The TNNI3 Arg145Trp variant has been identified in multiple HCM and RCM patients (Mogensen et al., 2003; Mogensen et al., 2004; Cheng, 2005; Fokstuen et … (more)
The TNNI3 Arg145Trp variant has been identified in multiple HCM and RCM patients (Mogensen et al., 2003; Mogensen et al., 2004; Cheng, 2005; Fokstuen et al., 2008; Andersen et al., 2009; van den Wjingaard et al., 2011). The variant has also been shown to segregate with disease in several families (Mogensen et al., 2004; Andersen et al., 2009; van den Wjingaard et al., 2011; Maron et al., 2012). Van den Wjingaard et al., identified this variant in multiple probands, and using haplotype analysis proved that TNNI3 Arg145Trp is a founder mutation in the Dutch population. Furthermore, functional studies have shown that Arg145Trp mutant muscle fibres cause a significant increase in Ca2+ sensitivity for force development as well as ATPase activity, and lack the ability to inhibit human cardiac troponin I actomyosin ATPase activity (Gomes AV, et al., 2005; Yumoto F, et al., 2005; Wu HF, et al., 2007; Wen Y, et al, 2007). The TNNI3 Arg145Trp variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/), at an allele frequency of 0.000012. We identified this variant in a HCM proband with no family history of disease or SCD. Two different rare variants at this position (Arg145Gly and Arg145Gln) have also been reported in multiple HCM individuals suggesting that an amino acid substitution at this site may not be tolerated. Computational tools SIFT, MutationTaster, Polyphen-HCM and PolyPhen-2 predict this variant to have a deleterious effect. Based on the adapted ACMG criteria (Kelly MA, et al., 2018), functional studies have shown that this variant causes a damaging effect on the protein (PS3), the variant has reported in more than 10 unrelated HCM probands (PS4), the variant segregates strongly with disease (PP1_Strong), the variant is rare in the general population (PM2) and multiple in silico tools predict this variant to have a deleterious effect (PP3), therefore we classify TNNI3 Arg145Trp 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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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001744846.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 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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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: SCV001979717.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 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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Outcomes of Contemporary Family Screening in Hypertrophic Cardiomyopathy. | van Velzen HG | Circulation. Genomic and precision medicine | 2018 | PMID: 29661763 |
Diverse Phenotypic Expression of Cardiomyopathies in a Family with TNNI3 p.Arg145Trp Mutation. | Hwang JW | Korean circulation journal | 2017 | PMID: 28382084 |
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 |
Restrictive Cardiomyopathy Troponin I R145W Mutation Does Not Perturb Myofilament Length-dependent Activation in Human Cardiac Sarcomeres. | Dvornikov AV | The Journal of biological chemistry | 2016 | PMID: 27557662 |
Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients with hypertrophic cardiomyopathy. | Wang J | European journal of heart failure | 2014 | PMID: 25132132 |
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 |
Double or compound sarcomere mutations in hypertrophic cardiomyopathy: a potential link to sudden death in the absence of conventional risk factors. | Maron BJ | Heart rhythm | 2012 | PMID: 21839045 |
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 |
Rapid detection of genetic variants in hypertrophic cardiomyopathy by custom DNA resequencing array in clinical practice. | Fokstuen S | Journal of medical genetics | 2011 | PMID: 21239446 |
Echocardiographic strain imaging to assess early and late consequences of sarcomere mutations in hypertrophic cardiomyopathy. | Ho CY | Circulation. Cardiovascular genetics | 2009 | PMID: 20031602 |
Functional effects of a restrictive-cardiomyopathy-linked cardiac troponin I mutation (R145W) in transgenic mice. | Wen Y | Journal of molecular biology | 2009 | PMID: 19651143 |
Some cardiomyopathy-causing troponin I mutations stabilize a functional intermediate actin state. | Mathur MC | Biophysical journal | 2009 | PMID: 19289050 |
Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives. | Andersen PS | Human mutation | 2009 | PMID: 19035361 |
Allele and species dependent contractile defects by restrictive and hypertrophic cardiomyopathy-linked troponin I mutants. | Davis J | Journal of molecular and cellular cardiology | 2008 | PMID: 18423659 |
A DNA resequencing array for pathogenic mutation detection in hypertrophic cardiomyopathy. | Fokstuen S | Human mutation | 2008 | PMID: 18409188 |
[Reduced Ca2+ current in rat cardiomyocytes transfected with troponin I R145W mutation gene]. | Wu HF | Zhonghua xin xue guan bing za zhi | 2007 | PMID: 18269819 |
Prevalence, clinical significance, and genetic basis of hypertrophic cardiomyopathy with restrictive phenotype. | Kubo T | Journal of the American College of Cardiology | 2007 | PMID: 17599605 |
Increased Ca2+ affinity of cardiac thin filaments reconstituted with cardiomyopathy-related mutant cardiac troponin I. | Kobayashi T | The Journal of biological chemistry | 2006 | PMID: 16531415 |
Drastic Ca2+ sensitization of myofilament associated with a small structural change in troponin I in inherited restrictive cardiomyopathy. | Yumoto F | Biochemical and biophysical research communications | 2005 | PMID: 16288990 |
Myocardial late gadolinium enhancement cardiovascular magnetic resonance in hypertrophic cardiomyopathy caused by mutations in troponin I. | Moon JC | Heart (British Cardiac Society) | 2005 | PMID: 16020591 |
Frequency of cardiac troponin I mutations in families with hypertrophic cardiomyopathy in China. | Cheng TO | Journal of the American College of Cardiology | 2005 | PMID: 15992656 |
Mutations in human cardiac troponin I that are associated with restrictive cardiomyopathy affect basal ATPase activity and the calcium sensitivity of force development. | Gomes AV | The Journal of biological chemistry | 2005 | PMID: 15961398 |
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 |
Comparison of fluorescent SSCP and denaturing HPLC analysis with direct sequencing for mutation screening in hypertrophic cardiomyopathy. | Mogensen J | Journal of medical genetics | 2003 | PMID: 12746413 |
Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. | Mogensen J | The Journal of clinical investigation | 2003 | PMID: 12531876 |
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 |
Troponin I: inhibitor or facilitator. | Perry SV | Molecular and cellular biochemistry | 1999 | PMID: 10098965 |
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 rs104894724 ...
HelpRecord last updated Oct 13, 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.