ClinVar Genomic variation as it relates to human health
NM_001276345.2(TNNT2):c.452G>A (p.Arg151Gln)
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(2); Likely pathogenic(3); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001276345.2(TNNT2):c.452G>A (p.Arg151Gln)
Variation ID: 181617 Accession: VCV000181617.31
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1q32.1 1: 201364335 (GRCh38) [ NCBI UCSC ] 1: 201333463 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 May 1, 2024 Jan 6, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001276345.2:c.452G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001263274.1:p.Arg151Gln missense NM_000364.4:c.452G>A NP_000355.2:p.Arg151Gln missense NM_001001430.3:c.422G>A NP_001001430.1:p.Arg141Gln missense NM_001001431.3:c.422G>A NP_001001431.1:p.Arg141Gln missense NM_001001432.3:c.407G>A NP_001001432.1:p.Arg136Gln missense NM_001276346.2:c.332G>A NP_001263275.1:p.Arg111Gln missense NM_001276347.2:c.422G>A NP_001263276.1:p.Arg141Gln missense NC_000001.11:g.201364335C>T NC_000001.10:g.201333463C>T NG_007556.1:g.18343G>A LRG_431:g.18343G>A LRG_431t1:c.452G>A LRG_431p1:p.Arg151Gln - Protein change
- R141Q, R151Q, R111Q, R136Q
- Other names
- p.R141Q:CGG>CAG
- Canonical SPDI
- NC_000001.11:201364334:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
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. |
|||
TNNT2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
954 | 972 |
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. |
---|---|---|---|---|
Likely pathogenic (1) |
criteria provided, single submitter
|
Aug 14, 2023 | RCV000159297.6 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Dec 18, 2023 | RCV000768722.9 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jan 6, 2024 | RCV000796707.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Jan 3, 2022 | RCV001808433.1 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Feb 8, 2022 | RCV002326911.2 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jun 1, 2023 | RCV003319182.1 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Nov 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000900092.2 First in ClinVar: May 06, 2019 Last updated: Jan 01, 2022 |
|
|
Likely pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 2
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058521.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TNNT2 related disorder (ClinVar ID: VCV000181617, PS1_P). A … (more)
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TNNT2 related disorder (ClinVar ID: VCV000181617, PS1_P). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012414, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.98, PP3_P). A missense variant is a common mechanism associated with Cardiomyopathy (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Left ventricular hypertrophy (present)
|
|
Pathogenic
(Jun 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Primary dilated cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University
Accession: SCV003932368.1
First in ClinVar: Aug 05, 2023 Last updated: Aug 05, 2023 |
|
|
Likely pathogenic
(Aug 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000209243.13
First in ClinVar: Feb 24, 2015 Last updated: Aug 31, 2023 |
Comment:
Identified in multiple unrelated patients with cardiomyopathy referred for genetic testing at GeneDx and in published literature (Cuenca et al., 2016; Wang et al., 2020); … (more)
Identified in multiple unrelated patients with cardiomyopathy referred for genetic testing at GeneDx and in published literature (Cuenca et al., 2016; Wang et al., 2020); 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: 19466586, 28007021, 26656454, 24367593, 23539503, 21846512, 15769782, 14654368, 11684629, 24992688, 31589614, 26899768, 34350506, 34428338, 30105547, 34135346, 33996946) (less)
|
|
Pathogenic
(Jan 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Invitae
Accession: SCV000936231.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 141 of the TNNT2 protein (p.Arg141Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 141 of the TNNT2 protein (p.Arg141Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of arrhythmogenic cardiomyopathy and/or dilated cardiomyopathy (PMID: 19466586, 26899768; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 181617). 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%. This variant disrupts the p.Arg141 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11684629, 14654368, 15769782, 21846512, 23539503, 24367593, 24992688, 26656454). 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)
|
|
Uncertain Significance
(Dec 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004827753.1
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)
|
Comment:
This missense variant replaces arginine with glutamine at codon 141 of the TNNT2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with glutamine at codon 141 of the TNNT2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 26899768, 34350506; communication with external laboratories: ClinVar SCV000209243.12, SCV000936231.5; Variation ID: 181617); one of these individuals also carried a pathogenic truncation variant the TTN gene (PMID: 26899768). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 19645627, 22429680, 25524337). This variant has also been reported in multiple individuals not known to be affected with TNNT2-related disorders (PMID: 28007021, 28706299, 32355288, 34135346) This variant has been identified in 2/250100 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg141Trp, is considered to be disease-causing (ClinVar variation ID: 12414), suggesting that arginine at this position is important for TNNT2 protein function. Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 6
|
|
Likely pathogenic
(Dec 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001342179.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with glutamine at codon 141 in the tropomyosin binding domain 1 of the TNNT2 protein. Computational prediction tools indicate that … (more)
This missense variant replaces arginine with glutamine at codon 141 in the tropomyosin binding domain 1 of the TNNT2 protein. Computational prediction tools indicate that this variant may have a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least ten individuals affected with dilated cardiomyopathy (PMID: 26899768, 33996946, 34350506, 36252119; communication with external laboratories: ClinVar SCV000209243.12, SCV000936231.5; Variation ID: 181617); one of these individuals also carried a pathogenic truncation variant the TTN gene (PMID: 26899768). This variant has been shown to segregate with disease in two affected individuals in one family (PMID: 36252119). This variant has also been reported in seven individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 19645627, 22429680, 25524337) and in one individual affected with sudden cardiac death (PMID: 27332903). This variant has been identified in 2/250100 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg141Trp, is reported as disease-causing (ClinVar variation ID: 12414), indicating that arginine at this position is important for TNNT2 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
|
|
Uncertain significance
(Feb 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002629658.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R141Q variant (also known as c.422G>A), located in coding exon 9 of the TNNT2 gene, results from a G to A substitution at nucleotide … (more)
The p.R141Q variant (also known as c.422G>A), located in coding exon 9 of the TNNT2 gene, results from a G to A substitution at nucleotide position 422. The arginine at codon 141 is replaced by glutamine, an amino acid with highly similar properties. This variant was detected in a family with dilated cardiomyopathy (DCM) where the affected individuals also had a co-occurring TTN nonsense variant (Cuenca S et al. J. Heart Lung Transplant., 2016 05;35:625-35). This variant was also detected in a DCM cohort, as well as exome and targeted sequencing cohorts not selected for cardiomyopathy; however details were limited (Rani DS et al. Abstract #311,Genomic Med, 2008 Dec;2:303-30; Kwak SH et al. Exp. Mol. Med., 2017 07;49:e356; (Lacaze P et al. NPJ Genom Med, 2021 Jun;6:51). Another alteration affecting this codon (R141W, c.421C>T) has been reported in association with DCM (Villard E et al. Eur. Heart J. 2005 Apr;26(8):794-803). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
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 |
---|---|---|---|---|
Genetic Basis of Childhood Cardiomyopathy. | Bagnall RD | Circulation. Genomic and precision medicine | 2022 | PMID: 36252119 |
Next-Generation Sequencing Reveals Novel Genetic Variants for Dilated Cardiomyopathy in Pediatric Chinese Patients. | Wang Y | Pediatric cardiology | 2022 | PMID: 34350506 |
Genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of European descent. | Lacaze P | NPJ genomic medicine | 2021 | PMID: 34135346 |
Clinical Significance of Variants in the TTN Gene in a Large Cohort of Patients With Sporadic Dilated Cardiomyopathy. | Xiao L | Frontiers in cardiovascular medicine | 2021 | PMID: 33996946 |
Actionable secondary findings in 1116 Hong Kong Chinese based on exome sequencing data. | Yu MHC | Journal of human genetics | 2021 | PMID: 33223521 |
The ChinaMAP analytics of deep whole genome sequences in 10,588 individuals. | Cao Y | Cell research | 2020 | PMID: 32355288 |
Findings of a 1303 Korean whole-exome sequencing study. | Kwak SH | Experimental & molecular medicine | 2017 | PMID: 28706299 |
Implementation of next generation sequencing into pediatric hematology-oncology practice: moving beyond actionable alterations. | Oberg JA | Genome medicine | 2016 | PMID: 28007021 |
A Prospective Study of Sudden Cardiac Death among Children and Young Adults. | Bagnall RD | The New England journal of medicine | 2016 | PMID: 27332903 |
Genetic basis of familial dilated cardiomyopathy patients undergoing heart transplantation. | Cuenca S | The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation | 2016 | PMID: 26899768 |
Exome Sequencing Identifies Pathogenic and Modifier Mutations in a Child With Sporadic Dilated Cardiomyopathy. | Long PA | Journal of the American Heart Association | 2015 | PMID: 26656454 |
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 |
A novel arginine to tryptophan (R144W) mutation in troponin T (cTnT) gene in an indian multigenerational family with dilated cardiomyopathy (FDCM). | Rani DS | PloS one | 2014 | PMID: 24992688 |
Effects of troponin T cardiomyopathy mutations on the calcium sensitivity of the regulated thin filament and the actomyosin cross-bridge kinetics of human β-cardiac myosin. | Sommese RF | PloS one | 2013 | PMID: 24367593 |
Familial dilated cardiomyopathy mutations uncouple troponin I phosphorylation from changes in myofibrillar Ca²⁺ sensitivity. | Memo M | Cardiovascular research | 2013 | PMID: 23539503 |
High resolution melting: improvements in the genetic diagnosis of hypertrophic cardiomyopathy in a Portuguese cohort. | Santos S | BMC medical genetics | 2012 | PMID: 22429680 |
Clinical and mutational spectrum in a cohort of 105 unrelated patients with dilated cardiomyopathy. | Millat G | European journal of medical genetics | 2011 | PMID: 21846512 |
Low prevalence and variable clinical presentation of troponin I and troponin T gene mutations in hypertrophic cardiomyopathy. | Curila K | Genetic testing and molecular biomarkers | 2009 | PMID: 19645627 |
Genomics of complex disorders I. | - | Genomic medicine | 2008 | PMID: 19466586 |
Mutation screening in dilated cardiomyopathy: prominent role of the beta myosin heavy chain gene. | Villard E | European heart journal | 2005 | PMID: 15769782 |
Cardiac troponin T mutation R141W found in dilated cardiomyopathy stabilizes the troponin T-tropomyosin interaction and causes a Ca2+ desensitization. | Lu QW | Journal of molecular and cellular cardiology | 2003 | PMID: 14654368 |
Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. | Richard P | Circulation | 2003 | PMID: 12707239 |
Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy. | Li D | Circulation | 2001 | PMID: 11684629 |
[The disease pattern of the diffuse, nesidioblastic hyperplasia of the pancreatic islets in newborn and infants (author's transl)]. | Jeschke R | Klinische Padiatrie | 1978 | PMID: 209243 |
[Radiation burden resulting from implanted cardiac pacemakers with 238Pu-nuclide batteries]. | Piesch E | Strahlenschutz in Forschung und Praxis | 1976 | PMID: 936231 |
[An autopsy case of liver cell carcinoma with bone metastases and a relatively long clinical course (author's transl)]. | Kusakabe A | Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology | 1976 | PMID: 181617 |
click to load more click to collapse |
Text-mined citations for rs730881101 ...
HelpRecord last updated May 08, 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.