ClinVar Genomic variation as it relates to human health
NM_001276345.2(TNNT2):c.311G>T (p.Arg104Leu)
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>T (p.Arg104Leu)
Variation ID: 43629 Accession: VCV000043629.18
- 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 May 29, 2016 Feb 28, 2024 Oct 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001276345.2:c.311G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001263274.1:p.Arg104Leu missense NM_000364.4:c.311G>T NP_000355.2:p.Arg104Leu missense NM_001001430.3:c.281G>T NP_001001430.1:p.Arg94Leu missense NM_001001431.3:c.281G>T NP_001001431.1:p.Arg94Leu missense NM_001001432.3:c.266G>T NP_001001432.1:p.Arg89Leu missense NM_001276346.2:c.291+319G>T intron variant NM_001276347.2:c.281G>T NP_001263276.1:p.Arg94Leu missense NC_000001.11:g.201365291C>A NC_000001.10:g.201334419C>A NG_007556.1:g.17387G>T LRG_431:g.17387G>T LRG_431t1:c.311G>T LRG_431p1:p.Arg104Leu - Protein change
- R104L, R94L, R89L
- Other names
- p.R94L:CGC>CTC
- Canonical SPDI
- NC_000001.11:201365290:C: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.
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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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TNNT2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
898 | 917 |
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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Likely pathogenic (1) |
criteria provided, single submitter
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Mar 19, 2018 | RCV000036576.7 | |
Pathogenic (2) |
criteria provided, single submitter
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May 20, 2022 | RCV000159284.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 29, 2018 | RCV000619398.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 17, 2023 | RCV000468546.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 31, 2019 | RCV001258056.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003450686.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003450687.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003450688.1 |
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
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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
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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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Pathogenic
(May 20, 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: SCV000209230.11
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrated altered calcium regulation of muscle contraction (Lu et al., 2003; Harada et al., 2004); In silico analysis supports that this missense … (more)
Published functional studies demonstrated altered calcium regulation of muscle contraction (Lu et al., 2003; Harada et al., 2004); 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: 14654368, 10525521, 28073646, 22144547, 27532257, 11606294, 14722098, 18258667, 23074333, 25611685, 32659924, 30165862, 20513729) (less)
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Likely pathogenic
(Mar 19, 2018)
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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: SCV000060231.6
First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 1
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Likely pathogenic
(Dec 31, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial hypertrophic cardiomyopathy 2
Dilated cardiomyopathy 1D
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434887.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The c.281G>T variant results in an amino acid change from an arginine to a leucine at codon 94 of the TNNT2 protein (p.Arg94Leu). The variant … (more)
The c.281G>T variant results in an amino acid change from an arginine to a leucine at codon 94 of the TNNT2 protein (p.Arg94Leu). The variant has been reported in an individual with familial hypertrophic cardiomyopathy (HCM) and segregates in the family (PMID: 10525521). It has also been reported in multiple unrelated individuals affected with HCM (PMID: 27532257). Functional studies support an effect of this variant on calcium-dependent force generation (PMID: 14654368). Different missense variants at this location (p.Arg94Cys, p.Arg94His) have been reported in association with HCM (PMID: 22112859, 23711808, 2003160, 20624503). This variant is not present in population databases (gnomAD). Therefore, this variant in the TNNT2 gene is classified as likely pathogenic. (less)
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Pathogenic
(Jan 29, 2018)
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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: SCV000740033.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.R94L pathogenic mutation (also known as c.281G>T), located in coding exon 8 of the TNNT2 gene, results from a G to T substitution at … (more)
The p.R94L pathogenic mutation (also known as c.281G>T), located in coding exon 8 of the TNNT2 gene, results from a G to T substitution at nucleotide position 281. The arginine at codon 94 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in several hypertrophic cardiomyopathy (HCM) cohorts and has been shown to segregate with disease in one small family (Varnava A et al. Heart. 1999;82:621-4; Melacini P et al. Eur Heart J. 2010 Sep;31(17):2111-23; Pasquale F et al. Circ Cardiovasc Genet. 2012 Feb;5(1):10-7). Functional in vitro analyses involving skinned cardiac fibers have suggested that this alteration affects TNNT2 protein function (Lu QW et al. J Mol Cell Cardiol. 2003;35:1421-7). In addition, alterations involving the same amino acid, p.R94C (c.280C>T) and p.R94H (c.281G>A), have been described in patients with HCM including de novo occurrences (D'Cruz LG et al. J Med Genet. 2000;37:E18; Millat G et al. Eur J Med Genet. 2010;53:261-7). 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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Likely 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: SCV004181483.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Likely 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: SCV004181481.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Likely 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: SCV004181482.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Oct 17, 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: SCV000541917.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 94 of the TNNT2 protein (p.Arg94Leu). … (more)
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 94 of the TNNT2 protein (p.Arg94Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 10525521, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43629). 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. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 14654368, 14722098). 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: 10978365). 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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Likely pathogenic
(Sep 03, 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: SCV000280519.1
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. TNNT2 variant Arg94Leu (R94L; c.281G>T at the nucleotide level) The variant has been reported in at least 3 unrelated cases of HCM with moderate segregation data in one family and functional data available. Varnava et al. (1999, 2001) identified this variant in an HCM family with a history of four SCD under age 45. It segregated with the disease in 3 affected family members tested, which included two siblings and their cousin. In addition, a child of one of the siblings who had an abnormal ECG but normal echo at age 6 also had the variant. Melacini et al. (2010) detected the variant in an Italian HCM transplant patient. Pasquale et al. (2011) detected it in an HCM patient followed in the UK. Another change at this same codon, Arg94Cys, has been associated with HCM (we consider that variant to be of uncertain significance, probably disease causing). Variation at nearby loci of TNNT2 (within 10 amino acids to either side) has been associated with disease, supporting the functional importance of this region of the protein. These HCM variants include Val85Leu, Asp86Ala, Arg92Trp, Arg92Gln, Arg92Leu, Lys97Asn and Ala104Val (Willott et al. 2010; Harvard Sarcomere Protein Gene Mutation Database). The region between residues ~80-180 of TNNT2 has been described as essential for anchoring the troponin-tropomyosin complex to the thin filament (Hinkle et al. 1999, Palm et al. 2001). In vitro functional data from Palm et al. (2001) suggests that the Arg94Leu variant impairs binding of troponin T to tropomyosin and makes the protein less effective at promoting the binding of tropomyosin to actin. Lu et al. (2003) found it increased the calcium sensitivity of force generation, but had no effect on the protein’s affinity for tropomyosin. Harada & Potter (2004) showed the variant to alter the contractile properties of skinned cardiac fibers, including the response of cardiac contraction to changes in pH. This is a nonconservative amino acid change from a basic, positively-charged Arginine to a nonpolar Leucine. The Arginine at codon 94 is completely conserved across 39 vertebrate species examined. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging”. Pasquale et al. (2011) report that the SIFT prediction for the variant is “not tolerated”. In total the variant has not been seen in ~6190 published controls and publicly available population datasets. There is no variation at codon 94 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~3500 Caucasian and ~1800 African American individuals (as of 1/15/2012). There is no variation at this codon listed in dbSNP or 1000 genomes (as of 1/15/2012). The variant was not observed in published controls: Varnava et al. (1999) did not find the variant in 100 normal controls. Varnava et al. (2001) did not detect it in at least 90 control individuals. Melacini et al. (2010) did not find it in 400 (Italian?) controls. Pasquale et al. (2011) did not find it in 200 Caucasian controls. (less)
Number of individuals with the variant: 3
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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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Hypertrophic Cardiomyopathy Without Ventricular Hypertrophy: Usefulness of Genetic and Pathological Study in Preventing Sudden Death. | Segura-Villalobos F | Revista espanola de cardiologia (English ed.) | 2017 | PMID: 28073646 |
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 |
Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. | Alfares AA | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25611685 |
Cardiac structural and sarcomere genes associated with cardiomyopathy exhibit marked intolerance of genetic variation. | Pan S | Circulation. Cardiovascular genetics | 2012 | PMID: 23074333 |
Long-term outcomes in hypertrophic cardiomyopathy caused by mutations in the cardiac troponin T gene. | Pasquale F | Circulation. Cardiovascular genetics | 2012 | PMID: 22144547 |
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 |
Clinicopathological profiles of progressive heart failure in hypertrophic cardiomyopathy. | Melacini P | European heart journal | 2010 | PMID: 20513729 |
Array-based resequencing assay for mutations causing hypertrophic cardiomyopathy. | Waldmüller S | Clinical chemistry | 2008 | PMID: 18258667 |
Familial hypertrophic cardiomyopathy mutations from different functional regions of troponin T result in different effects on the pH and Ca2+ sensitivity of cardiac muscle contraction. | Harada K | The Journal of biological chemistry | 2004 | PMID: 14722098 |
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 |
Disease-causing mutations in cardiac troponin T: identification of a critical tropomyosin-binding region. | Palm T | Biophysical journal | 2001 | PMID: 11606294 |
Hypertrophic cardiomyopathy: histopathological features of sudden death in cardiac troponin T disease. | Varnava AM | Circulation | 2001 | PMID: 11560853 |
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 |
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Text-mined citations for rs397516457 ...
HelpRecord last updated Mar 05, 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.