ClinVar Genomic variation as it relates to human health
NM_001276345.2(TNNT2):c.360T>G (p.Phe120Leu)
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.360T>G (p.Phe120Leu)
Variation ID: 177807 Accession: VCV000177807.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q32.1 1: 201365242 (GRCh38) [ NCBI UCSC ] 1: 201334370 (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 Jun 1, 2016 Feb 28, 2024 Jan 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001276345.2:c.360T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001263274.1:p.Phe120Leu missense NM_000364.4:c.360T>G NP_000355.2:p.Phe120Leu missense NM_001001430.3:c.330T>G NP_001001430.1:p.Phe110Leu missense NM_001001431.3:c.330T>G NP_001001431.1:p.Phe110Leu missense NM_001001432.3:c.315T>G NP_001001432.1:p.Phe105Leu missense NM_001276346.2:c.291+368T>G intron variant NM_001276347.2:c.330T>G NP_001263276.1:p.Phe110Leu missense NC_000001.11:g.201365242A>C NC_000001.10:g.201334370A>C NG_007556.1:g.17436T>G LRG_431:g.17436T>G LRG_431t1:c.360T>G LRG_431p1:p.Phe120Leu - Protein change
- F110L, F120L, F105L
- Other names
- p.F110L:TTT>TTG
- Canonical SPDI
- NC_000001.11:201365241:A:C
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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), exomes 0.00001
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 |
898 | 917 |
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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Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2018 | RCV000159288.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 24, 2017 | RCV000211744.6 | |
Likely pathogenic (1) |
no assertion criteria provided
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Feb 8, 2013 | RCV000824804.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 9, 2018 | RCV001089627.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003453158.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 27, 2023 | RCV003531982.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 21, 2024 | RCV003764947.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003453157.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003453159.1 |
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
(Jul 24, 2017)
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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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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000740432.1
First in ClinVar: Jun 01, 2016 Last updated: Jun 01, 2016 |
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Likely pathogenic
(Nov 27, 2018)
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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: SCV000209234.13
First in ClinVar: Feb 24, 2015 Last updated: Apr 17, 2019 |
Comment:
The F110L variant that is likely pathogenic in the TNNT2 gene has previously been reported in association with HCM and was found to segregate with … (more)
The F110L variant that is likely pathogenic in the TNNT2 gene has previously been reported in association with HCM and was found to segregate with HCM in at least three affected relatives from one family (Torricelli et al., 2003; Girolami et al., 2006; Olivotto et al., 2008; Coppini et al., 2014). Of note, a different nucleotide change resulting in the same amino acid substitution (c.328 T>C, p.F110L) has also been reported, and some publications only describe the variant at the protein level and do not specify the nucleotide substitution. The F110L (c.330 T>G) is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although the F110L variant is a conservative amino acid substitution, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, a different likely pathogenic missense variants at the same residue (F110I) has also been reported in association with HCM (Watkins et al., 1995; Anan et al., 1998; Yanaga et al., 1999; Konno et al., 2005). (less)
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Likely pathogenic
(Feb 09, 2018)
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criteria provided, single submitter
Method: research
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Hypertrophic cardiomyopathy
Wolff-Parkinson-White pattern (Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV001245104.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
Comment:
TNNT2 Phe110Leu had been previously identified in multiple HCM probands (Walsh R, et al., 2017; Coppini R, et al., 2014; GeneDx, Pers. Comm.) and in … (more)
TNNT2 Phe110Leu had been previously identified in multiple HCM probands (Walsh R, et al., 2017; Coppini R, et al., 2014; GeneDx, Pers. Comm.) and in one family it was found to segregate to two affected family members (Torricelli F, et al., 2003). We identified this variant in 1 HCM proband and an affected parent. The proband also harbours a second mutation MYBPC3 p.Gly531Arg. The TNNT2 Phe110Leu variant is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). In silico tools SIFT, PolyPhen-2 and MutationTaster predict that this variant is deleterious. In summary, the variant has been reported in numerous cases, it is very rare in the general population, in silico tools predict the variant to impact protein function and the variant has segregated with disease in one family, therefore we classify TNNT2 Phe110Leu as 'Likely Pathogenic'. (less)
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Pathogenic
(Jan 21, 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: SCV004569383.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 110 of the TNNT2 protein (p.Phe110Leu). … (more)
This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 110 of the TNNT2 protein (p.Phe110Leu). This variant is present in population databases (rs727504331, gnomAD 0.004%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 14636924, 25524337). ClinVar contains an entry for this variant (Variation ID: 177807). 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: 33025817). This variant disrupts the p.Phe110 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9714088, 16115869, 33025817). 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 08, 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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Blueprint Genetics
Accession: SCV000927398.1
First in ClinVar: Jul 24, 2019 Last updated: Jul 24, 2019 |
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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: SCV004181442.1
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: SCV004181443.1
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: SCV004181444.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Likely pathogenic
(Jul 27, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV004359942.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces phenylalanine with leucine at codon 110 in the tropomyosin binding domain of the TNNT2 protein. Computational prediction suggests that this variant … (more)
This missense variant replaces phenylalanine with leucine at codon 110 in the tropomyosin binding domain of the TNNT2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 14636924, 23074333, 27532257, 29875424, 23074333, 27532257, 29875424, 35514357). It has been shown that this variant segregates with disease in 3 affected individuals in one family (PMID: 14636924, 16858239, 18533079). This variant has also been reported in an individual affected with hypertrophic cardiomyopathy and left ventricular systolic dysfunction who also carried a pathogenic variant in the MYBPC3 gene (PMID: 32228044). This variant has been identified in 2/251494 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Phe110Ile, is considered to be disease-causing (ClinVar variation ID: 12412), suggesting that phenylalanine at this position is important for TNNT2 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Likely pathogenic
(Feb 08, 2013)
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no assertion criteria provided
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: SCV000204106.4
First in ClinVar: Jan 31, 2015 Last updated: Aug 26, 2019 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 4
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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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Genotype-Driven Pathogenesis of Atrial Fibrillation in Hypertrophic Cardiomyopathy: The Case of Different TNNT2 Mutations. | Pioner JM | Frontiers in physiology | 2022 | PMID: 35514357 |
Development of a Cardiac Sarcomere Functional Genomics Platform to Enable Scalable Interrogation of Human TNNT2 Variants. | Pettinato AM | Circulation | 2020 | PMID: 33025817 |
Hypertrophic Cardiomyopathy With Left Ventricular Systolic Dysfunction: Insights From the SHaRe Registry. | Marstrand P | Circulation | 2020 | PMID: 32228044 |
Defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center. | Mazzarotto F | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29875424 |
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 |
Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations. | Coppini R | Journal of the American College of Cardiology | 2014 | PMID: 25524337 |
Cardiac structural and sarcomere genes associated with cardiomyopathy exhibit marked intolerance of genetic variation. | Pan S | Circulation. Cardiovascular genetics | 2012 | PMID: 23074333 |
Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. | Olivotto I | Mayo Clinic proceedings | 2008 | PMID: 18533079 |
A molecular screening strategy based on beta-myosin heavy chain, cardiac myosin binding protein C and troponin T genes in Italian patients with hypertrophic cardiomyopathy. | Girolami F | Journal of cardiovascular medicine (Hagerstown, Md.) | 2006 | PMID: 16858239 |
F110I and R278C troponin T mutations that cause familial hypertrophic cardiomyopathy affect muscle contraction in transgenic mice and reconstituted human cardiac fibers. | Hernandez OM | The Journal of biological chemistry | 2005 | PMID: 16115869 |
Prevalence and clinical profile of troponin T mutations among patients with hypertrophic cardiomyopathy in tuscany. | Torricelli F | The American journal of cardiology | 2003 | PMID: 14636924 |
Patients with familial hypertrophic cardiomyopathy caused by a Phe110Ile missense mutation in the cardiac troponin T gene have variable cardiac morphologies and a favorable prognosis. | Anan R | Circulation | 1998 | PMID: 9714088 |
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Text-mined citations for rs727504331 ...
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.