ClinVar Genomic variation as it relates to human health
NM_000363.5(TNNI3):c.292C>T (p.Arg98Ter)
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(1); 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.292C>T (p.Arg98Ter)
Variation ID: 181575 Accession: VCV000181575.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.42 19: 55154821 (GRCh38) [ NCBI UCSC ] 19: 55666189 (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 Oct 9, 2016 Feb 20, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000363.5:c.292C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000354.4:p.Arg98Ter nonsense NC_000019.10:g.55154821G>A NC_000019.9:g.55666189G>A NG_007866.2:g.7912C>T LRG_432:g.7912C>T LRG_432t1:c.292C>T - Protein change
- R98*
- Other names
- p.R98X:CGA>TGA
- Canonical SPDI
- NC_000019.10:55154820: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00006
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
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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
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 | 723 |
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
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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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May 26, 2023 | RCV000159212.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 25, 2024 | RCV000628957.10 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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May 11, 2023 | RCV001170620.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 29, 2021 | RCV002478481.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 30, 2022 | RCV003162667.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Apr 05, 2018)
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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: SCV001333210.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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Uncertain significance
(Dec 30, 2022)
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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: SCV003869178.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Comment:
The p.R98* variant (also known as c.292C>T), located in coding exon 6 of the TNNI3 gene, results from a C to T substitution at nucleotide … (more)
The p.R98* variant (also known as c.292C>T), located in coding exon 6 of the TNNI3 gene, results from a C to T substitution at nucleotide position 292. This changes the amino acid from an arginine to a stop codon within coding exon 6. This variant has been detected in individuals from cohorts with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) (Bollen IAE et al. J Physiol, 2017 Jul;595:4677-4693; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Lu C et al. J Transl Med, 2018 Aug;16:241; Gran F et al. Eur J Pediatr, 2022 Jan;181:287-294). This variant has also been detected in a stillbirth case and in a participant of the Framingham Heart Study without overt signs of cardiomyopathy; however, clinical details were limited (Bick AG et al. Am J Hum Genet, 2012 Sep;91:513-9; Sahlin E et al. PLoS One, 2019 Jan;14:e0210017). Functional studies from one group suggest this variant may alter calcium sensitivity; however, the physiological relevance of this finding is unclear (Bollen IAE et al. J Physiol, 2017 Jul;595:4677-4693). Truncating alterations in TNNI3 have been reported in patients with restrictive cardiomyopathy (RCM) and hypertrophic cardiomyopathy (HCM) (Kaski JP et al. Heart. 2008;94(11):1478-84; Kostareva A et al. Int J Cardiol. 2009;131(3):410-2; Olivotto I et al. J Am Coll Cardiol. 2011;58(8):839-48; van den Wijngaard A et al. Neth Heart J. 2011;19(7-8):344-51). 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 26, 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: SCV000209158.14
First in ClinVar: Feb 24, 2015 Last updated: Jun 03, 2023 |
Comment:
Reported in association with cardiomyopathy, however, additional clinical information was not provided (Walsh et al., 2017; Lu et al., 2018); Reported in a participant in … (more)
Reported in association with cardiomyopathy, however, additional clinical information was not provided (Walsh et al., 2017; Lu et al., 2018); Reported in a participant in the Framingham heart study (FHS) who had a normal left ventricular wall thickness and a physiological risk factor for heart disease (Bick et al., 2012); Nonsense 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; This variant is associated with the following publications: (PMID: 22958901, 27532257, 28436080, 30165862) (less)
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Uncertain significance
(May 11, 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: SCV001357930.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 6 of the TNNI3 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 6 of the TNNI3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. An experimental functional study has shown that this variant may cause reduced protein expression and increased Ca2+-sensitivity (PMID: 28436080). However, clinical relevance of this observation is not clear. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID 28436080, 30165862, 34286374), in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257), and in a fetus affected with stillbirth (PMID: 30615648). This variant has also been reported in homozygosity in an infant affected with early-onset dilated cardiomyopathy (PMID: 36981019); both heterozygous parents were apparently unaffected but did not receive cardiological evaluations. This variant has been identified in 16/280804 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
(Jan 25, 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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Invitae
Accession: SCV000749866.8
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg98*) 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.Arg98*) 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 (rs730881068, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with autosomal recessive dilated cardiomyopathy (PMID: 36252119, 36981019). ClinVar contains an entry for this variant (Variation ID: 181575). For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Oct 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy, familial restrictive, 1
Dilated cardiomyopathy 2A Dilated cardiomyopathy 1FF Hypertrophic cardiomyopathy 7
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002787942.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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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 |
Genetic Basis of Childhood Cardiomyopathy. | Bagnall RD | Circulation. Genomic and precision medicine | 2022 | PMID: 36252119 |
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 |
Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3. | Kühnisch J | Clinical genetics | 2019 | PMID: 31568572 |
Identification of putative pathogenic single nucleotide variants (SNVs) in genes associated with heart disease in 290 cases of stillbirth. | Sahlin E | PloS one | 2019 | PMID: 30615648 |
Molecular analysis of inherited cardiomyopathy using next generation semiconductor sequencing technologies. | Lu C | Journal of translational medicine | 2018 | PMID: 30165862 |
Genotype-specific pathogenic effects in human dilated cardiomyopathy. | Bollen IAE | The Journal of physiology | 2017 | PMID: 28436080 |
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 |
Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts. | Bick AG | American journal of human genetics | 2012 | PMID: 22958901 |
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Text-mined citations for rs730881068 ...
HelpRecord last updated Feb 28, 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.