ClinVar Genomic variation as it relates to human health
NM_001276345.2(TNNT2):c.310C>T (p.Arg104Cys)
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.310C>T (p.Arg104Cys)
Variation ID: 165549 Accession: VCV000165549.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q32.1 1: 201365292 (GRCh38) [ NCBI UCSC ] 1: 201334420 (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 2, 2015 Feb 28, 2024 Jan 14, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001276345.2:c.310C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001263274.1:p.Arg104Cys missense NM_000364.4:c.310C>T NP_000355.2:p.Arg104Cys missense NM_001001430.3:c.280C>T NP_001001430.1:p.Arg94Cys missense NM_001001431.3:c.280C>T NP_001001431.1:p.Arg94Cys missense NM_001001432.3:c.265C>T NP_001001432.1:p.Arg89Cys missense NM_001276346.2:c.291+318C>T intron variant NM_001276347.2:c.280C>T NP_001263276.1:p.Arg94Cys missense NC_000001.11:g.201365292G>A NC_000001.10:g.201334420G>A NG_007556.1:g.17386C>T LRG_431:g.17386C>T LRG_431t1:c.310C>T LRG_431p1:p.Arg104Cys - Protein change
- R104C, R94C, R89C
- Other names
- p.R94C:CGC>TGC
- Canonical SPDI
- NC_000001.11:201365291: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.
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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 |
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
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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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Likely pathogenic (1) |
criteria provided, single submitter
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Jan 22, 2014 | RCV000152104.4 | |
Pathogenic (2) |
criteria provided, single submitter
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Aug 21, 2017 | RCV000159282.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 5, 2022 | RCV000619541.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 14, 2024 | RCV000533469.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 6, 2019 | RCV001193334.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003453110.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003453111.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003453109.1 |
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
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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
(Aug 21, 2017)
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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: SCV000209228.12
First in ClinVar: Feb 24, 2015 Last updated: May 30, 2018 |
Comment:
p.Arg94Cys (CGC>TGC): c.280 C>T in exon 9 of the TNNT2 gene (NM_001001430.1). The Arg94Cys mutation in the TNNT2 gene has been reported in association with … (more)
p.Arg94Cys (CGC>TGC): c.280 C>T in exon 9 of the TNNT2 gene (NM_001001430.1). The Arg94Cys mutation in the TNNT2 gene has been reported in association with HCM (D'Cruz L et al., 2000). D'Cruz et al. reported Arg94Cys as a de novo mutation in a female patient with HCM and it was not observed in 120 control individuals. Additionally, the Arg94Cys mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Other mutations at this codon (Arg94His, Arg94Leu) and in nearby residues (Arg92Gln, Arg92Leu, Arg92Trp, Glu96Lys) have been reported in association in association with cardiomyopathy, further supporting the functional importance of this region of the protein. In summary, Arg94Cys in the TNNT2 gene is interpreted as a disease-causing mutation. Hereditary hypertrophic cardiomyopathy (HCM) is primarily an autosomal dominant disease characterized by myocardial hypertrophy in the absence of other cardiac or systemic causes. HCM is most frequently caused by mutations in genes coding for sarcomeric proteins in the cardiac muscle leading to myocyte disarray, a hallmark feature of HCM. Less commonly, ventricular hypertrophy is a presenting feature of genetic systemic disorders, such as Danon disease, Fabry disease, or mitochondrial cardiomyopathy. HCM has a variable clinical presentation; including palpitations, chest pain, heart failure syncope, or sudden death, although some individuals may be asymptomatic (Marian A et al., 1995; Maron B, 2002). Mutations in the TNNT2 gene have been reported in 5-15% of patients with autosomal dominant familial hypertrophic cardiomyopathy, often characterized by minimal left ventricular hypertrophy (LVH) but a high incidence of sudden cardiac death (Moolman J et al., 1997; Cirino A et al., 2011). Mutations in TNNT2 have been reported less frequently in association with autosomal dominant familial dilated cardiomyopathy (Hershberger R et al., 2009). The variant is found in HCM panel(s). (less)
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Likely pathogenic
(Jan 22, 2014)
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criteria provided, single submitter
Method: clinical testing
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Restrictive 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: SCV000200768.5
First in ClinVar: Feb 02, 2015 Last updated: Feb 02, 2015 |
Comment:
The Arg94Cys variant in TNNT2 has not been previously reported in individuals wi th cardiomyopathy or in large population studies. It has been detected in … (more)
The Arg94Cys variant in TNNT2 has not been previously reported in individuals wi th cardiomyopathy or in large population studies. It has been detected in 1 chil d with RCM tested by our laboratory and parental testing revealed de novo occur rence, which strongly supports a pathogenic role. Arginine (Arg) at position 94 is highly conserved in evolution and the change to cysteine (Cys) was predicted to be pathogenic using a computational tool clinically validated by our laborato ry. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In addition, 2 other likely disease-causing variants at this pos ition (Arg94His and Arg94Leu) have been reported in multiple individuals with HC M (Varnava 1999, LMM unpublished data). In summary, the low frequency, computati onal prediction for this variant, and presence of other disease-causing variants at this position all suggest that the Arg94Cys variant is likely to be pathogen ic, but additional studies are needed to fully establish its clinical significan ce. (less)
Number of individuals with the variant: 1
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Pathogenic
(Sep 06, 2019)
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criteria provided, single submitter
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362085.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: TNNT2 c.280C>T (p.Arg94Cys) results in a non-conservative amino acid change located in the T1 domain of the encoded protein sequence. Five of five … (more)
Variant summary: TNNT2 c.280C>T (p.Arg94Cys) results in a non-conservative amino acid change located in the T1 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251458 control chromosomes. c.280C>T has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy, one of whom was reportedly a proband with a de-novo occurrence of this variant (D'Cruz_2012, Otsuka_2012, Liu_2013). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported, although mutations spanning residues 92-110 of TNNT2 have been reported to impair tropomyosin-dependent functions of troponin T (Palm_2001) supporting a critical domain function. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 05, 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: SCV000736122.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.R94C pathogenic mutation (also known as c.280C>T), located in coding exon 8 of the TNNT2 gene, results from a C to T substitution at … (more)
The p.R94C pathogenic mutation (also known as c.280C>T), located in coding exon 8 of the TNNT2 gene, results from a C to T substitution at nucleotide position 280. The arginine at codon 94 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been detected as a confirmed de novo alteration in one individual with hypertrophic cardiomyopathy (HCM) (D'Cruz LG et al. J Med Genet. 2000;37:E18). This mutation has also been reported in several other unrelated HCM cases and in one restrictive cardiomyopathy (RCM) case (Otsuka H et al. Circ J. 2012;76:453-61; Liu W et al. Am J Cardiol. 2013;112:585-9; Berge KE et al. Clin Genet. 2014;86:355-60; Hayashi T et al. J. Hum. Genet., 2018 Sep;63:989-996). Two alterations affecting the same amino acid, p.R94H and p.R94L, have also been reported in association with HCM (Varnava A et al. Heart. 1999;82:621-4; Ripoll-Vera T et al. Rev Esp Cardiol (Engl Ed). 2016;69:149-58). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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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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: SCV004181488.1
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: SCV004181489.1
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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Hypertrophic cardiomyopathy 2
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004181490.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Jan 14, 2024)
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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: SCV000644768.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 94 of the TNNT2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 94 of the TNNT2 protein (p.Arg94Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 10978365, 22112859, 23711808, 24111713; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 165549). 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.Arg94 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10525521, 14654368, 14722098, 20031602, 20624503, 23283745). 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
(Jan 16, 2012)
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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: SCV000280518.1
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. p.Arg94Cys (R94C; c.280C>T) in the TNNT2 gene This Arg94Cys variant has been reported in at least 2 unrelated cases of HCM—with no segregation or functional data available. Arg94Cys was first reported by D’Cruz et al. (2000), and was de novo in the HCM patient. Both parents tested negative for the variant and had normal EKGs and echocardiograms. Paternity was genetically confirmed. The paper showed the variant to be due to the C>T transition of a methylated cytosine in a CpG dinucleotide. Mogensen et al. (J Med Genet 2003 May;40(5):e59) apparently identified Arg94Cys in an HCM patient as part of a comparative study of two sequencing methods. However, the variant is not listed in the published paper itself, and the website link given for supplementary data is nonfunctional—so this could not be confirmed. (It is unclear if this is the same case.) Otsuka et al. (2011) found it in one Japanese proband. There is no published segregation data available. Another variant at this same codon Arg94Leu has been reported multiple times in association with HCM (and of note, it has been seen to cause sudden death in the absence of significant hypertrophy: Varvana et al 1999) and we would consider it likely disease causing. In ClinVar, LMM notes that another variant at this same codon, Arg94His, has been associated with HCM in at least 4 patients and that in one case it was de novo. 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, Phe87Cys, Ile90Met, Arg92Trp, Arg92Gln, Arg92Leu, Lys97Asn and Ala104Val (HGMD; 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 a change at codon 94—specifically Arg94Leu—impairs binding of troponin T to tropomyosin, and makes the protein less effective at promoting the binding of tropomyosin to actin. This is a nonconservative amino acid change from a basic, positively-charged Arginine to a polar, neutral Cysteine (capable of forming disulfide bridges). 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”. In total the variant has not been seen in over 60,000 published controls and individuals from publicly available population datsets. 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: D’Cruz et al. (2000) did not detect Arg94Cys in 120 multiethnic controls. Otsuka et al. (2011) did not observe it in 200 Japanese controls. Our patient’s ancestry is from Vietnam, and ancestry-matched individuals can be found in greater numbers in the ExAC database of ~60,000 exomes from disease-specific and population genetic studies (with efforts made to exclude individuals with severe pediatric diseases). ExAC contains individuals from multiple ethnic backgrounds (Latino, European (non-Finnish), Finnish, South Asian, African & East Asian), including 4295 East Asians and 8256 South Asians. This variant is not present in ExAC. (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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Genetic background of Japanese patients with pediatric hypertrophic and restrictive cardiomyopathy. | Hayashi T | Journal of human genetics | 2018 | PMID: 29907873 |
Troponins, intrinsic disorder, and cardiomyopathy. | Na I | Biological chemistry | 2016 | PMID: 27074551 |
Genetics of hypertrophic cardiomyopathy in Norway. | Berge KE | Clinical genetics | 2014 | PMID: 24111713 |
Mutation spectrum in a large cohort of unrelated Chinese patients with hypertrophic cardiomyopathy. | Liu W | The American journal of cardiology | 2013 | PMID: 23711808 |
Multiple gene mutations, not the type of mutation, are the modifier of left ventricle hypertrophy in patients with hypertrophic cardiomyopathy. | Zou Y | Molecular biology reports | 2013 | PMID: 23283745 |
Prevalence and distribution of sarcomeric gene mutations in Japanese patients with familial hypertrophic cardiomyopathy. | Otsuka H | Circulation journal : official journal of the Japanese Circulation Society | 2012 | PMID: 22112859 |
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 |
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 |
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 rs727503513 ...
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.