ClinVar Genomic variation as it relates to human health
NM_001276345.2(TNNT2):c.517G>A (p.Glu173Lys)
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(1); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001276345.2(TNNT2):c.517G>A (p.Glu173Lys)
Variation ID: 567696 Accession: VCV000567696.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q32.1 1: 201363379 (GRCh38) [ NCBI UCSC ] 1: 201332507 (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 Oct 10, 2018 May 1, 2024 Aug 9, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001276345.2:c.517G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001263274.1:p.Glu173Lys missense NM_000364.4:c.517G>A NP_000355.2:p.Glu173Lys missense NM_001001430.3:c.487G>A NP_001001430.1:p.Glu163Lys missense NM_001001431.3:c.487G>A NP_001001431.1:p.Glu163Lys missense NM_001001432.3:c.472G>A NP_001001432.1:p.Glu158Lys missense NM_001276346.2:c.397G>A NP_001263275.1:p.Glu133Lys missense NM_001276347.2:c.487G>A NP_001263276.1:p.Glu163Lys missense NC_000001.11:g.201363379C>T NC_000001.10:g.201332507C>T NG_007556.1:g.19299G>A LRG_431:g.19299G>A LRG_431t1:c.517G>A LRG_431p1:p.Glu173Lys - Protein change
- E163K, E173K, E133K, E158K
- Other names
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- Canonical SPDI
- NC_000001.11:201363378:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
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
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 |
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. |
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Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 9, 2022 | RCV000687856.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 7, 2020 | RCV002331334.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 31, 2022 | RCV003150329.2 |
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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Likely pathogenic
(Sep 27, 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: SCV002809804.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(May 31, 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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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV003838078.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Pathogenic
(Aug 09, 2022)
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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: SCV000815445.5
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
Experimental studies have shown that this missense change affects TNNT2 function (PMID: 10617660, 14722098, 22579624, 24367593, 24480310). For these reasons, this variant has been classified … (more)
Experimental studies have shown that this missense change affects TNNT2 function (PMID: 10617660, 14722098, 22579624, 24367593, 24480310). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 567696). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 7898523, 22112859, 29398688; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 163 of the TNNT2 protein (p.Glu163Lys). (less)
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Uncertain significance
(Dec 07, 2020)
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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: SCV002633853.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.E163K variant (also known as c.487G>A), located in coding exon 10 of the TNNT2 gene, results from a G to A substitution at nucleotide … (more)
The p.E163K variant (also known as c.487G>A), located in coding exon 10 of the TNNT2 gene, results from a G to A substitution at nucleotide position 487. The glutamic acid at codon 163 is replaced by lysine, an amino acid with similar properties. This alteration has been detected in multiple individuals with hypertrophic cardiomyopathy (Watkins H et al. N Engl J Med, 1995 Apr;332:1058-64; Pasquale F et al. Circ Cardiovasc Genet, 2012 Feb;5:10-7; Otsuka H et al. Circ J, 2012 Nov;76:453-61; Walsh R et al. Genet Med, 2017 02;19:192-203; Teramoto R et al. Circ J, 2018 03;82:1139-1148). Experimental studies show that this alteration may impact calcium sensitivity and cardiac troponin T and tropomyosin interaction; however, the clinical significance of these studies is unclear (Szczesna D et al. J Biol Chem, 2000 Jan;275:624-30; Harada K et al. J Biol Chem, 2004 Apr;279:14488-95; Sommese RF et al. PLoS One, 2013 Dec;8:e83403; Manning EP et al. J Mol Biol, 2012 Aug;421:54-66; Moore RK et al. Arch Biochem Biophys, 2014 Jun;552-553:21-8). In vitro assays using human induced pluripotent stem cell-derived cardiomyocytes have shown that this variant results in gene expression and contractility changes similar to those seen with pathogenic TNNT2 variants (Pettinato AM et al. Circulation. 2020 Dec;142(23):2262-2275). Based on internal structural analysis, p.E163K disrupts a highly conserved region known to mediate allosteric communications critical to proper function (Lu QW et al. J Geriatr Cardiol. 2013 Mar;10(1):91-101; Moore RK et al. J Mol Cell Cardiol. 2013 May;58:188-98). This amino acid position is well 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)
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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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Late Gadolinium Enhancement for Prediction of Mutation-Positive Hypertrophic Cardiomyopathy on the Basis of Panel-Wide Sequencing. | Teramoto R | Circulation journal : official journal of the Japanese Circulation Society | 2018 | PMID: 29398688 |
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 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Allosteric effects of cardiac troponin TNT1 mutations on actomyosin binding: a novel pathogenic mechanism for hypertrophic cardiomyopathy. | Moore RK | Archives of biochemistry and biophysics | 2014 | PMID: 24480310 |
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 |
Molecular effects of familial hypertrophic cardiomyopathy-related mutations in the TNT1 domain of cTnT. | Manning EP | Journal of molecular biology | 2012 | PMID: 22579624 |
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 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 |
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 |
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 |
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 |
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Text-mined citations for rs1558225569 ...
HelpRecord last updated May 01, 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.