ClinVar Genomic variation as it relates to human health
NM_001276345.2(TNNT2):c.304C>T (p.Arg102Trp)
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.304C>T (p.Arg102Trp)
Variation ID: 43627 Accession: VCV000043627.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q32.1 1: 201334426 (GRCh37) [ NCBI UCSC ] 1: 201365298 (GRCh38) [ 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 Apr 20, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001276345.2:c.304C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001263274.1:p.Arg102Trp missense NM_000364.4:c.304C>T NP_000355.2:p.Arg102Trp missense NM_001001430.3:c.274C>T NP_001001430.1:p.Arg92Trp missense NM_001001431.3:c.274C>T NP_001001431.1:p.Arg92Trp missense NM_001001432.3:c.259C>T NP_001001432.1:p.Arg87Trp missense NM_001276346.2:c.291+312C>T intron variant NM_001276347.2:c.274C>T NP_001263276.1:p.Arg92Trp missense NC_000001.11:g.201365298G>A NC_000001.10:g.201334426G>A NG_007556.1:g.17380C>T LRG_431:g.17380C>T LRG_431t1:c.304C>T LRG_431p1:p.Arg102Trp P45379:p.Arg102Trp - Protein change
- R102W, R92W, R87W
- Other names
- p.R92W:CGG>TGG
- Canonical SPDI
- NC_000001.11:201365297: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00000
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 | ||
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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. |
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TNNT2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
946 | 964 |
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. |
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Pathogenic (5) |
criteria provided, single submitter
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Oct 28, 2022 | RCV000159280.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 5, 2015 | RCV000208103.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 30, 2024 | RCV000474512.11 | |
Pathogenic (1) |
criteria provided, single submitter
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May 2, 2022 | RCV000620701.2 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 10, 2023 | RCV000768491.7 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2023 | RCV001807762.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003450682.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003450681.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2023 | RCV003486557.2 |
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
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, University of Leuven
Accession: SCV000886796.1
First in ClinVar: May 02, 2019 Last updated: May 02, 2019 |
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Pathogenic
(May 02, 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: SCV000739951.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.R92W pathogenic mutation (also known as c.274C>T), located in coding exon 8 of the TNNT2 gene, results from a C to T substitution at … (more)
The p.R92W pathogenic mutation (also known as c.274C>T), located in coding exon 8 of the TNNT2 gene, results from a C to T substitution at nucleotide position 274. The arginine at codon 92 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in multiple patients with hypertrophic cardiomyopathy (HCM) and has shown strong segregation with the disease (Moolman JC et al, J. Am. Coll. Cardiol. 1997 Mar; 29(3):549-55; Moolman-Smook JC et al, Am. J. Hum. Genet. 1999 Nov; 65(5):1308-20; Varnava AM et al, Circulation 2001 Sep; 104(12):1380-4; Ackerman MJ et al, J. Am. Coll. Cardiol. 2002 Jun; 39(12):2042-8; Fujino N et al, Clin Cardiol 2001 May; 24(5):397-402; Van Driest SL et al, Circulation 2003 Jul; 108(4):445-51). In addition, in vitro studies suggest this alteration might interfere with tropomycin binding (Palm T et al, Biophys. J. 2001 Nov; 81(5):2827-37; Harada K et al, J. Biol. Chem. 2004 Apr; 279(15):14488-95). 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 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 2
Dilated cardiomyopathy 1D Cardiomyopathy, familial restrictive, 3
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002815780.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Dec 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV004359945.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with tryptophan at codon 92 in the tropomyosin binding domain 1 of the TNNT2 protein. Computational prediction suggests that this … (more)
This missense variant replaces arginine with tryptophan at codon 92 in the tropomyosin binding domain 1 of the TNNT2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies using in vitro modeling have shown that this variant may result in impaired tropomyosin binding (PMID: 11606294, 14722098). Additionally, functional studies using mouse models have demonstrated systolic dysfunction and decreased ventricular mass (PMID: 16326803). This variant has been reported in over 15 individuals affected with hypertrophic cardiomyopathy (PMID: 9060892, 10521296, 11346248, 11560853, 12084606, 12860912, 20414521, 22321274, 23494605, 28615295, 29572196, 9060892, 11346248 23494605, 29572196). It has been shown that this variant segregates with disease in multiple affected family members across multiple families (PMID: 9060892, 11346248 23494605, 29572196). A different variant occurring at the same codon, p.Arg92Gln, is a well documented pathogenic mutation (Clinvar variation ID: 12409), indicating that arginine at this position is important for TNNT2 protein function. This variant has been identified in 2/282802 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Jan 30, 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: SCV000541909.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 92 of the TNNT2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 92 of the TNNT2 protein (p.Arg92Trp). This variant is present in population databases (rs397516456, gnomAD 0.0009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 8951566, 9060892, 26507537). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43627). 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: 14722098, 22334656). This variant disrupts the p.Arg92 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7898523, 8205619, 9201030, 10085122, 10617660, 14722098, 18403758). 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
(Apr 10, 2023)
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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: SCV004816574.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces arginine with tryptophan at codon 92 in the tropomyosin binding domain 1 of the TNNT2 protein. Computational prediction suggests that this … (more)
This missense variant replaces arginine with tryptophan at codon 92 in the tropomyosin binding domain 1 of the TNNT2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies using in vitro modeling have shown that this variant may result in impaired tropomyosin binding (PMID: 11606294, 14722098). Additionally, functional studies using mouse models have demonstrated systolic dysfunction and decreased ventricular mass (PMID: 16326803). This variant has been reported in over 15 individuals affected with hypertrophic cardiomyopathy (PMID: 9060892, 10521296, 11346248, 11560853, 12084606, 12860912, 20414521, 22321274, 23494605, 28615295, 29572196, 9060892, 11346248 23494605, 29572196). It has been shown that this variant segregates with disease in multiple affected family members across multiple families (PMID: 9060892, 11346248 23494605, 29572196). A different variant occurring at the same codon, p.Arg92Gln, is a well documented pathogenic mutation (Clinvar variation ID: 12409), indicating that arginine at this position is important for TNNT2 protein function. This variant has been identified in 2/282802 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Nov 05, 2015)
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criteria provided, single submitter
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000264252.3
First in ClinVar: Feb 27, 2016 Last updated: Apr 15, 2023 |
Number of individuals with the variant: 1
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Pathogenic
(Apr 01, 2015)
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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: SCV000060228.6
First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019 |
Comment:
The p.Arg92Trp variant in TNNT2 has been reported in the literature and by our l aboratory in >20 individuals with HCM and segregated with disease … (more)
The p.Arg92Trp variant in TNNT2 has been reported in the literature and by our l aboratory in >20 individuals with HCM and segregated with disease in >15 affecte d relatives from >5 families (Koga 1996, Ackerman 2002, Moolman 1997, Moolman-Sm ook 1999, Fujino 2001, Varnava 2001, Van Driest 2003, Marsiglia 2010, Yang 2011, Fujita 2013; LMM unpublished data). This variant has been identified in 1/66730 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs397516456). Please note that for diseases with clini cal variability or reduced penetrance, pathogenic variants may be present at a l ow frequency in the general population. In vitro functional studies and mouse mo dels provide evidence that the p.Arg92Trp variant impacts protein function (Palm 2001, Harada 2004, Ertz-berger 2005, Manning 2012). In summary, this variant me ets our criteria to be classified as pathogenic for HCM in an autosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM) based upon segregatio n studies and functional evidence. (less)
Number of individuals with the variant: 11
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 2
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058465.1
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 as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000043627, PS1_S). The variant … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000043627, PS1_S). The variant was co-segregated with Cardiomyopathy, hypertrophic, 2 in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 9060892, 8951566, 26507537) (PP1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 14722098, 22334656, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.835, 3CNET: 0.997, 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: 0.000007, PM2_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012409, PM5_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Left ventricular hypertrophy (present)
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Pathogenic
(Oct 28, 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: SCV000209226.14
First in ClinVar: Feb 24, 2015 Last updated: Apr 09, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Functional studies indicate R92W disrupts tropomyosin binding and increases calcium sensitivity of the cardiac thin … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Functional studies indicate R92W disrupts tropomyosin binding and increases calcium sensitivity of the cardiac thin filament (Palm et al., 2001, Harada et al., 2004; Revera et al., 2008, Manning et al., 2012a, Manning et al., 2012b); 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: 11606294, 22579624, 21310275, 18029407, 19880069, 26955724, 22334656, 10521296, 12860912, 27590665, 28166811, 27532257, 26507537, 30025578, 28202948, 29563334, 16326803, 31513939, 29572196, 33025817, 14722098, 31006259, 33996946, 30847666, 31737537, 33673806, 11346248, 35626289, 35208637, 9060892, 8951566) (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: SCV004181494.1
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: SCV004181496.1
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
|
Genome-Nilou Lab
Accession: SCV004181497.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Mar 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV004239775.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Jul 02, 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: SCV000280515.1
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 Arg92Trp (R92W; at the nucleotide level) This variant has been reported in at least 16 unrelated cases of HCM with good segregation data in 2 families and weak segregation data in two more. Strong functional data is available both in vitro and in a transgenic mouse model. Koga et al. (1996) found Arg92Trp in two Japanese HCM families. The variant was “present in all affected family members” (a total of 5 people), but specific segregation data for each family is not provided. Moolman et al. (1997) detected this variant in 2 South African families of mixed ancestry with HCM. Segregation data was available for one of these families, with five affected family members carrying the variant. Moolman-Smook et al. (1999) detected it in 4 additional HCM probands of mixed ancestry from South Africa. Varnava et al. (2001) detected it in 2 unrelated cases. Fujino et al. (2001)/Shimizu et al. (2003) identified it in 2 Japanese families. In one family, Arg92Trp segregated with disease in 6 affected family members (5 siblings and one of their children). In the other, two affected siblings carried the variant. Ackerman et al. (2002) detected it in one HCM patient at the Mayo Clinic; it segregated with disease in the patient and her mother. Waldmuller et al. (2002) used this variant in developing a microarray screen for recurring HCM variants. Van Driest et al (2003) detected it in another HCM case at the Mayo Clinic. Van Driest et al. (2004) reported a double-heterozygote carrying Arg92Trp plus a Val256Ile variant in MYBPC3. Konno et al. (2005) detected it in 8 Japanese individuals from HCM families (it is not clear if they are related, or how many have LVH).***note that the cases reported in Van Driest et al (2003, 2004) and Ackerman et al (2002) may overlap. Some authors have suggested that p.Arg92Trp in TNNT2 is associated with a higher risk of sudden death with mild or even absent hypertrophy (Moolman et al 1997, 1999). Two other mutations at the same codon have also been reported in families with HCM: p.Arg92Leu and p.Arg92Gln (we categorize both as very likely 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 Glu83Lys, Val85Leu, Asp86Ala, Arg94Leu, Arg94Cys, and Lys97Asn (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 92—whether Arg92Trp, Arg92Gln or Arg92Leu—impairs binding of troponin T to tropomyosin, and makes the protein less effective at promoting the binding of tropomyosin to actin. Harada & Potter (2004) showed the Arg92Trp variant to alter the contractile properties of skinned cardiac fibers, including the response of cardiac contraction to changes in pH. He et al. (2007) showed that transgenic mice bearing the Arg92Trp or Arg92Leu variant had a greater “energy cost” for cardiac muscle contraction than wild-type mice. The magnitude of these changes was mutation-specific: Arg92Trp hearts showed more severe energetic abnormalities and greater contractile dysfunction than Arg92Leu hearts. Guinto et al. (2009) showed diastolic dysfunction in transgenic mice carrying the variant, and altered calcium kinetics in isolated transgenic myocytes. This is a nonconservative amino acid change from a basic, positively-charged Arginine to a nonpolar Tryptophan. The Arginine at codon 92 is highly conserved across 39 vertebrate species examined (it is a Lysine in medaka) and surrounding residues are also highly conserved. 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 ~5990 published controls and publicly available population datsets. There is no variation at codon 92 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 also no variation at this codon listed in dbSNP or 1000 genomes (as of 1/15/2012). The variant was not observed in published controls: Koga et al. (1996) did not detect the variant in more than 100 Japanese controls. Moolman et al. (1997) reported that the variant was absent from 100 control individuals. Moolman-Smook et al. (1999) did not find it in 100 controls (unclear if these were the same controls as in 1997). Fujino et al. (2001) did not detect it in 100 controls. Varnava et al. (2001) did not detect it in at least 90 control individuals. Van Driest et al. (2003) did not detect it in 100 Caucasian and 100 African American controls. (less)
Number of individuals with the variant: 10
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001917468.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001930094.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001954196.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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Familial Hypertrophic Cardiomyopathy - Identification of cause and risk stratification through exome sequencing. | Biswas A | Gene | 2018 | PMID: 29572196 |
Burden of Recurrent and Ancestral Mutations in Families With Hypertrophic Cardiomyopathy. | Ross SB | Circulation. Cardiovascular genetics | 2017 | PMID: 28615295 |
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 |
Mutations in the cardiac troponin T gene show various prognoses in Japanese patients with hypertrophic cardiomyopathy. | Fujita E | Heart and vessels | 2013 | PMID: 23494605 |
Molecular effects of familial hypertrophic cardiomyopathy-related mutations in the TNT1 domain of cTnT. | Manning EP | Journal of molecular biology | 2012 | PMID: 22579624 |
Correlation of molecular and functional effects of mutations in cardiac troponin T linked to familial hypertrophic cardiomyopathy: an integrative in silico/in vitro approach. | Manning EP | The Journal of biological chemistry | 2012 | PMID: 22334656 |
[Novel mutations of cardiac troponin T in Chinese patients with hypertrophic cardiomyopathy]. | Yang J | Zhonghua xin xue guan bing za zhi | 2011 | PMID: 22321274 |
[Study of mutations causing hypertrophic cardiomyopathy in a group of patients from Espirito Santo, Brazil]. | Marsiglia JD | Arquivos brasileiros de cardiologia | 2010 | PMID: 20414521 |
Abnormal blood pressure response to exercise occurs more frequently in hypertrophic cardiomyopathy patients with the R92W troponin T mutation than in those with myosin mutations. | Heradien M | Heart rhythm | 2009 | PMID: 19880069 |
Shared genetic causes of cardiac hypertrophy in children and adults. | Morita H | The New England journal of medicine | 2008 | PMID: 18403758 |
Troponin T and beta-myosin mutations have distinct cardiac functional effects in hypertrophic cardiomyopathy patients without hypertrophy. | Revera M | Cardiovascular research | 2008 | PMID: 18029407 |
Long-term follow-up of R403WMYH7 and R92WTNNT2 HCM families: mutations determine left ventricular dimensions but not wall thickness during disease progression. | Revera M | Cardiovascular journal of Africa | 2007 | PMID: 17612745 |
Changes in the chemical and dynamic properties of cardiac troponin T cause discrete cardiomyopathies in transgenic mice. | Ertz-Berger BR | Proceedings of the National Academy of Sciences of the United States of America | 2005 | PMID: 16326803 |
Phenotypic differences between electrocardiographic and echocardiographic determination of hypertrophic cardiomyopathy in genetically affected subjects. | Konno T | Journal of internal medicine | 2005 | PMID: 16115294 |
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 |
Autopsy findings in siblings with hypertrophic cardiomyopathy caused by Arg92Trp mutation in the cardiac troponin T gene showing dilated cardiomyopathy-like features. | Shimizu M | Clinical cardiology | 2003 | PMID: 14640471 |
Prevalence and spectrum of thin filament mutations in an outpatient referral population with hypertrophic cardiomyopathy. | Van Driest SL | Circulation | 2003 | PMID: 12860912 |
Prevalence and age-dependence of malignant mutations in the beta-myosin heavy chain and troponin T genes in hypertrophic cardiomyopathy: a comprehensive outpatient perspective. | Ackerman MJ | Journal of the American College of Cardiology | 2002 | PMID: 12084606 |
Low-density DNA microarrays are versatile tools to screen for known mutations in hypertrophic cardiomyopathy. | Waldmüller S | Human mutation | 2002 | PMID: 11968089 |
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 |
Cardiac troponin T Arg92Trp mutation and progression from hypertrophic to dilated cardiomyopathy. | Fujino N | Clinical cardiology | 2001 | PMID: 11346248 |
Altered regulation of cardiac muscle contraction by troponin T mutations that cause familial hypertrophic cardiomyopathy. | Szczesna D | The Journal of biological chemistry | 2000 | PMID: 10617660 |
The origins of hypertrophic cardiomyopathy-causing mutations in two South African subpopulations: a unique profile of both independent and founder events. | Moolman-Smook JC | American journal of human genetics | 1999 | PMID: 10521296 |
Ca2+ sensitization and potentiation of the maximum level of myofibrillar ATPase activity caused by mutations of troponin T found in familial hypertrophic cardiomyopathy. | Yanaga F | The Journal of biological chemistry | 1999 | PMID: 10085122 |
Expression of a mutant (Arg92Gln) human cardiac troponin T, known to cause hypertrophic cardiomyopathy, impairs adult cardiac myocyte contractility. | Marian AJ | Circulation research | 1997 | PMID: 9201030 |
Sudden death due to troponin T mutations. | Moolman JC | Journal of the American College of Cardiology | 1997 | PMID: 9060892 |
Clinical manifestations of hypertrophic cardiomyopathy with mutations in the cardiac beta-myosin heavy chain gene or cardiac troponin T gene. | Koga Y | Journal of cardiac failure | 1996 | PMID: 8951566 |
Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. | Watkins H | The New England journal of medicine | 1995 | PMID: 7898523 |
Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. | Thierfelder L | Cell | 1994 | PMID: 8205619 |
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Text-mined citations for rs397516456 ...
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.