ClinVar Genomic variation as it relates to human health
NM_001276345.2(TNNT2):c.311G>A (p.Arg104His)
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_001276345.2(TNNT2):c.311G>A (p.Arg104His)
Variation ID: 43628 Accession: VCV000043628.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q32.1 1: 201365291 (GRCh38) [ NCBI UCSC ] 1: 201334419 (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 Feb 24, 2015 Apr 20, 2024 Jan 8, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001276345.2:c.311G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001263274.1:p.Arg104His missense NM_000364.4:c.311G>A NP_000355.2:p.Arg104His missense NM_001001430.3:c.281G>A NP_001001430.1:p.Arg94His missense NM_001001431.3:c.281G>A NP_001001431.1:p.Arg94His missense NM_001001432.3:c.266G>A NP_001001432.1:p.Arg89His missense NM_001276346.2:c.291+319G>A intron variant NM_001276347.2:c.281G>A NP_001263276.1:p.Arg94His missense NC_000001.11:g.201365291C>T NC_000001.10:g.201334419C>T NG_007556.1:g.17387G>A LRG_431:g.17387G>A LRG_431t1:c.311G>A LRG_431p1:p.Arg104His - Protein change
- R104H, R94H, R89H
- Other names
- p.R94H:CGC>CAC
- Canonical SPDI
- NC_000001.11:201365290: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
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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TNNT2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
946 | 964 |
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
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
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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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Jan 8, 2024 | RCV000036575.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 21, 2023 | RCV000159283.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 21, 2023 | RCV000230630.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 13, 2022 | RCV000619351.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003450685.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003450684.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003450683.1 |
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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Pathogenic
(Jun 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: SCV000739953.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.R94H pathogenic mutation (also known as c.281G>A), located in coding exon 8 of the TNNT2 gene, results from a G to A substitution at … (more)
The p.R94H pathogenic mutation (also known as c.281G>A), located in coding exon 8 of the TNNT2 gene, results from a G to A substitution at nucleotide position 281. The arginine at codon 94 is replaced by histidine, an amino acid with highly similar properties. This variant was reported in multiple individuals diagnosed with hypertrophic cardiomyopathy (HCM), and co-segregation was observed in three affected relatives from two families (Ho CY et al. Circ Cardiovasc Genet. 2009;2:314-21; Ripoll-Vera T et al. Rev Esp Cardiol (Engl Ed) 2016;69:149-58; Jiménez-Jáimez J et al. Rev Esp Cardiol (Engl Ed), 2017 Oct;70:808-816). This alteration was also detected in one individual diagnosed with HCM in childhood, in whom this variant was noted to occur de novo and in the presence of an alteration in the MYH7 gene (Millat G et al. Eur J Med Genet 2010; 53:261-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this variant is in a functionally important region (motif) and near other pathogenic variants (Palm T et al. Biophys. J., 2001 Nov;81:2827-37; Gangadharan B et al. Proc. Natl. Acad. Sci. U.S.A., 2017 10;114:11115-11120). In addition, this alteration is predicted to be deleterious by in silico analysis. 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
(Nov 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy, familial restrictive, 3
Hypertrophic cardiomyopathy 2 Dilated cardiomyopathy 1D
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000285649.8
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 94 of the TNNT2 protein (p.Arg94His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 94 of the TNNT2 protein (p.Arg94His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 2003160, 20624503; Invitae). ClinVar contains an entry for this variant (Variation ID: 43628). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNNT2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 11606294). This variant disrupts the p.Arg94 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10525521, 10978365, 11606294). 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
(Jun 19, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060230.6
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
The p.Arg94His variant in TNNT2 has been reported in at least 6 individuals with HCM, including 3 de novo occurrences (Ho 2009, Millat 2010, Ripoll-Vera … (more)
The p.Arg94His variant in TNNT2 has been reported in at least 6 individuals with HCM, including 3 de novo occurrences (Ho 2009, Millat 2010, Ripoll-Vera 2016, W alsh 2016, LMM data, ClinVar Variation ID 43628). The variant also segregated wi th disease in 2 affected members of 1 family (Ripoll-Vera 2016), and was absent from large population studies. Arginine (Arg) at position 94 is highly conserved in mammals and across evolutionarily distant species and the change to histidin e (His) was predicted to be pathogenic using a computational tool clinically val idated by our laboratory. This tool's pathogenic prediction is estimated to be c orrect 94% of the time (Jordan 2011). In addition, 2 other likely disease-causin g variants at this position (p.Arg94Cys and p.Arg94Leu) have been reported in mu ltiple individuals with HCM (Varnava 1999, Walsh 2016). In summary, the p.Arg94H is variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner. (less)
Number of individuals with the variant: 6
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Pathogenic
(Jul 21, 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: SCV000209229.12
First in ClinVar: Feb 24, 2015 Last updated: Jul 29, 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: 25351510, 25524337, 20624503, 23283745, 11606294, 29398688, 10978365, 27532257, 26507537, 31308319, 31737537, 35653365, 33025817, 32746448, 33906374, 34076677, 35514357, 28566242, 20031602) (less)
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Pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1D
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004181485.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy, familial restrictive, 3
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004181486.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 2
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004181487.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Jan 08, 2024)
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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: SCV004839108.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces arginine with histidine at codon 94 in the tropomyosin binding domain 1 of the TNNT2 protein. Computational prediction suggests that this … (more)
This missense variant replaces arginine with histidine at codon 94 in the tropomyosin binding domain 1 of the TNNT2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 15 individuals affected with hypertrophic cardiomyopathy (PMID: 19659763, 20031602, 20624503, 25351510, 26507537, 27532257, 28566242, 31308319, 32746448, 35026164, 35581268, 36357925, 26507537, 28566242). It has been shown that this variant segregates with disease in 3 affected individuals across 2 families (PMID: 26507537, 28566242). In one family, this variant has been reported to occur de novo in an individual affected with hypertrophic cardiomyopathy and with no family history (PMID: 36357925). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Arg94Cys and p.Arg94Leu, are considered to be disease-causing (ClinVar variation ID: 165549 and 43629), suggesting that arginine at this position is important for TNNT2 protein function. Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 1
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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De novo and inherited variants in coding and regulatory regions in genetic cardiomyopathies. | Vadgama N | Human genomics | 2022 | PMID: 36357925 |
BRG1 is a biomarker of hypertrophic cardiomyopathy in human heart specimens. | Scherba JC | Scientific reports | 2022 | PMID: 35581268 |
The genetic architecture of pediatric cardiomyopathy. | Ware SM | American journal of human genetics | 2022 | PMID: 35026164 |
Genetic variant burden and adverse outcomes in pediatric cardiomyopathy. | Burstein DS | Pediatric research | 2021 | PMID: 32746448 |
Presence of Hypertrophic Cardiomyopathy Related Gene Mutations and Clinical Manifestations in Vietnamese Patients With Hypertrophic Cardiomyopathy. | Tran Vu MT | Circulation journal : official journal of the Japanese Circulation Society | 2019 | PMID: 31308319 |
Molecular mechanisms and structural features of cardiomyopathy-causing troponin T mutants in the tropomyosin overlap region. | Gangadharan B | Proceedings of the National Academy of Sciences of the United States of America | 2017 | PMID: 28973951 |
Clinical and Genetic Diagnosis of Nonischemic Sudden Cardiac Death. | Jiménez-Jáimez J | Revista espanola de cardiologia (English ed.) | 2017 | PMID: 28566242 |
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 |
Clinical and Prognostic Profiles of Cardiomyopathies Caused by Mutations in the Troponin T Gene. | Ripoll-Vera T | Revista espanola de cardiologia (English ed.) | 2016 | PMID: 26507537 |
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 |
Prevalence and spectrum of mutations in a cohort of 192 unrelated patients with hypertrophic cardiomyopathy. | Millat G | European journal of medical genetics | 2010 | PMID: 20624503 |
Echocardiographic strain imaging to assess early and late consequences of sarcomere mutations in hypertrophic cardiomyopathy. | Ho CY | Circulation. Cardiovascular genetics | 2009 | PMID: 20031602 |
A child cohort study from southern Italy enlarges the genetic spectrum of hypertrophic cardiomyopathy. | Frisso G | Clinical genetics | 2009 | PMID: 19659763 |
Disease-causing mutations in cardiac troponin T: identification of a critical tropomyosin-binding region. | Palm T | Biophysical journal | 2001 | PMID: 11606294 |
Cytosine methylation confers instability on the cardiac troponin T gene in hypertrophic cardiomyopathy. | D'Cruz LG | Journal of medical genetics | 2000 | PMID: 10978365 |
A new mutation of the cardiac troponin T gene causing familial hypertrophic cardiomyopathy without left ventricular hypertrophy. | Varnava A | Heart (British Cardiac Society) | 1999 | PMID: 10525521 |
The chromosome, its anatomy, and its aberrations. | Yang-Feng TL | Research publications - Association for Research in Nervous and Mental Disease | 1991 | PMID: 2003160 |
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Text-mined citations for rs397516457 ...
HelpRecord last updated Apr 20, 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.