ClinVar Genomic variation as it relates to human health
NM_000363.5(TNNI3):c.611G>A (p.Arg204His)
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.611G>A (p.Arg204His)
Variation ID: 177679 Accession: VCV000177679.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.42 19: 55151856 (GRCh38) [ NCBI UCSC ] 19: 55663224 (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 Feb 20, 2024 Jul 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000363.5:c.611G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000354.4:p.Arg204His missense NC_000019.10:g.55151856C>T NC_000019.9:g.55663224C>T NG_007866.2:g.10877G>A NG_011829.2:g.2383G>A LRG_432:g.10877G>A LRG_432t1:c.611G>A LRG_679:g.2383G>A P19429:p.Arg204His - Protein change
- R204H
- Other names
- p.R204H:CGC>CAC
- Canonical SPDI
- NC_000019.10:55151855:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TNNI3 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
688 | 748 |
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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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 5, 2020 | RCV000159249.9 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 19, 2021 | RCV000469008.15 | |
Pathogenic (1) |
no assertion criteria provided
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Aug 26, 2019 | RCV001254739.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 13, 2022 | RCV002354362.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 26, 2023 | RCV003407578.4 |
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
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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
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
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(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:
de novo
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Center for Human Genetics, University of Leuven
Accession: SCV000579527.1
First in ClinVar: Apr 17, 2017 Last updated: Apr 17, 2017 |
Comment:
ACMG score likely pathogenic
Observation 1:
Number of individuals with the variant: 1
Family history: no
Age: 30-39 years
Sex: female
Ethnicity/Population group: Caucasian
Geographic origin: Belgium
Comment on evidence:
Observed as de novo variant
Secondary finding: no
Observation 2:
Number of individuals with the variant: 1
Family history: no
Age: 20-29 years
Sex: female
Ethnicity/Population group: Asian-African
Geographic origin: Georgia-Morocco
Comment on evidence:
Observed as de novo variant
Secondary finding: no
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Pathogenic
(Mar 05, 2020)
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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: SCV000209195.13
First in ClinVar: Feb 24, 2015 Last updated: Apr 17, 2019 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); Functional studies demonstrated that R204H results in decreased interaction between cardiac troponin I and cardiac … (more)
Not observed in large population cohorts (Lek et al., 2016); Functional studies demonstrated that R204H results in decreased interaction between cardiac troponin I and cardiac troponin C and T (Doolan et al., 2005; Nguyen et al., 2016); 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: 15698845, 16199542, 18801787, 27895589, 20617149, 27930701, 20569525, 27532257, 24322056, 29176140, 31912959, 31737537) (less)
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Likely pathogenic
(Jul 26, 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: SCV004106928.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The TNNI3 c.611G>A variant is predicted to result in the amino acid substitution p.Arg204His. This variant was reported in the heterozygous state in patients with … (more)
The TNNI3 c.611G>A variant is predicted to result in the amino acid substitution p.Arg204His. This variant was reported in the heterozygous state in patients with arrhythmogenic disorders (Additional data, Marschall et al. 2019. PubMed ID: 31737537; Supplemental Tables, Walsh et al. 2017. PubMed ID: 27532257; Parrott et al. 2020. PubMed ID: 31912959; Ware et al. 2021. PubMed ID: 33906374). Functional studies showed that this variant impacts the protein function of Troponin I (Doolan et al. 2005. PubMed ID: 15698845). Of note, another missense variant affecting the same amino acid (p.Arg204Cys) has also been reported to be causative for hypertrophic cardiomyopathy (Ware et al. 2021. PubMed ID: 33906374). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. (less)
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Likely pathogenic
(May 15, 2015)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000203935.5
First in ClinVar: Jan 31, 2015 Last updated: Aug 26, 2019 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 3
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Pathogenic
(Nov 23, 2016)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002103281.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
PP3, PM2, PS2, PS3, PS4
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Pathogenic
(Jan 13, 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: SCV002661109.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R204H pathogenic mutation (also known as c.611G>A), located in coding exon 8 of the TNNI3 gene, results from a G to A substitution at … (more)
The p.R204H pathogenic mutation (also known as c.611G>A), located in coding exon 8 of the TNNI3 gene, results from a G to A substitution at nucleotide position 611. The arginine at codon 204 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in several unrelated cases with hypertrophic cardiomyopathy and restrictive cardiomyopathy, including reported de novo occurrences and pediatric-onset disease, and has shown some segregation with disease in families (Doolan A et al. J Mol Cell Cardiol, 2005 Feb;38:387-93; Ingles J et al. J Med Genet, 2005 Oct;42:e59; Gambarin FI et al. Heart, 2008 Oct;94:1257; Parvatiyar MS et al. J Biomed Biotechnol, 2010 Jun;2010:350706; Yang SW et al. Cardiol Young, 2010 Oct;20:574-6; Ding WH et al. Chin Med J (Engl), 2017 Dec;130:2823-2828; Robyns T et al. Eur J Hum Genet, 2017 12;25:1313-1323; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10; Walsh R et al. Genet Med, 2017 02;19:192-203; Maurizi N et al. JAMA Cardiol, 2018 06;3:520-525; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Parrott A et al. Am J Med Genet C Semin Med Genet, 2020 03;184:116-123). This variant has been reported to impact protein-protein interactions and calcium sensitivity in in vitro assays (Doolan A et al. J Mol Cell Cardiol, 2005 Feb;38:387-93; Nguyen S et al. Front Physiol, 2016 Nov;7:520). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(May 19, 2021)
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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: SCV000551899.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect TNNI3 protein function (PMID:¬†27895589). This variant has been … (more)
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect TNNI3 protein function (PMID: 27895589). This variant has been observed to be de novo in an individual affected with restrictive cardiomyopathy (PMID: 29176140) and has been reported in several individuals affected with this disease or hypertrophic cardiomyopathy (PMID: 20569525, 18801787, 15698845, 27532257). ClinVar contains an entry for this variant (Variation ID: 177679). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 204 of the TNNI3 protein (p.Arg204His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. (less)
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Pathogenic
(Aug 26, 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: SCV001430824.1
First in ClinVar: Aug 23, 2020 Last updated: Aug 23, 2020 |
Comment:
This variant has been identified in 1 HCM proband as part of our research program. Family screening identified two additional affected individuals, one family member … (more)
This variant has been identified in 1 HCM proband as part of our research program. Family screening identified two additional affected individuals, one family member was diagnosed with HCM and the other with RCM. The variant segregated to both affected family members (2 meiosis). For further information please feel free to contact us. (less)
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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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Investigation of de novo variation in pediatric cardiomyopathy. | Parrott A | American journal of medical genetics. Part C, Seminars in medical genetics | 2020 | PMID: 31912959 |
Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders. | Marschall C | Cardiovascular diagnosis and therapy | 2019 | PMID: 31737537 |
Long-term Outcomes of Pediatric-Onset Hypertrophic Cardiomyopathy and Age-Specific Risk Factors for Lethal Arrhythmic Events. | Maurizi N | JAMA cardiology | 2018 | PMID: 29710196 |
Repeat genetic testing with targeted capture sequencing in primary arrhythmia syndrome and cardiomyopathy. | Robyns T | European journal of human genetics : EJHG | 2017 | PMID: 29255176 |
Role of Whole-exome Sequencing in Phenotype Classification and Clinical Treatment of Pediatric Restrictive Cardiomyopathy. | Ding WH | Chinese medical journal | 2017 | PMID: 29176140 |
Burden of Recurrent and Ancestral Mutations in Families With Hypertrophic Cardiomyopathy. | Ross SB | Circulation. Cardiovascular genetics | 2017 | PMID: 28615295 |
Nonfamilial Hypertrophic Cardiomyopathy: Prevalence, Natural History, and Clinical Implications. | Ingles J | Circulation. Cardiovascular genetics | 2017 | PMID: 28408708 |
Sudden Arrhythmic Death During Exercise: A Post-Mortem Genetic Analysis. | Campuzano O | Sports medicine (Auckland, N.Z.) | 2017 | PMID: 28255936 |
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 |
Amino Acid Changes at Arginine 204 of Troponin I Result in Increased Calcium Sensitivity of Force Development. | Nguyen S | Frontiers in physiology | 2016 | PMID: 27895589 |
Cardiac troponin mutations and restrictive cardiomyopathy. | Parvatiyar MS | Journal of biomedicine & biotechnology | 2010 | PMID: 20617149 |
Ventricular septal defect and restrictive cardiomyopathy in a paediatric TNNI3 mutation carrier. | Yang SW | Cardiology in the young | 2010 | PMID: 20569525 |
Pure restrictive cardiomyopathy associated with cardiac troponin I gene mutation: mismatch between the lack of hypertrophy and the presence of disarray. | Gambarin FI | Heart (British Cardiac Society) | 2008 | PMID: 18801787 |
Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling. | Ingles J | Journal of medical genetics | 2005 | PMID: 16199542 |
Cardiac troponin I mutations in Australian families with hypertrophic cardiomyopathy: clinical, genetic and functional consequences. | Doolan A | Journal of molecular and cellular cardiology | 2005 | PMID: 15698845 |
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Text-mined citations for rs727504275 ...
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.