ClinVar Genomic variation as it relates to human health
NM_001276345.2(TNNT2):c.358T>A (p.Phe120Ile)
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.358T>A (p.Phe120Ile)
Variation ID: 12412 Accession: VCV000012412.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q32.1 1: 201365244 (GRCh38) [ NCBI UCSC ] 1: 201334372 (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 Apr 4, 2013 Dec 24, 2023 May 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001276345.2:c.358T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001263274.1:p.Phe120Ile missense NM_000364.4:c.358T>A NP_000355.2:p.Phe120Ile missense NM_001001430.3:c.328T>A NP_001001430.1:p.Phe110Ile missense NM_001001431.3:c.328T>A NP_001001431.1:p.Phe110Ile missense NM_001001432.3:c.313T>A NP_001001432.1:p.Phe105Ile missense NM_001276346.2:c.291+366T>A intron variant NM_001276347.2:c.328T>A NP_001263276.1:p.Phe110Ile missense NC_000001.11:g.201365244A>T NC_000001.10:g.201334372A>T NG_007556.1:g.17434T>A LRG_431:g.17434T>A LRG_431t1:c.358T>A LRG_431p1:p.Phe120Ile P45379:p.Phe120Ile - Protein change
- F110I, F120I, F105I
- Other names
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- Canonical SPDI
- NC_000001.11:201365243:A: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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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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Pathogenic (2) |
criteria provided, single submitter
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Apr 11, 2023 | RCV000013223.18 | |
Pathogenic (1) |
no assertion criteria provided
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Jan 30, 2013 | RCV000223682.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2023 | RCV000709767.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 15, 2023 | RCV001804727.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003450627.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Nov 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1D
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000840077.1
First in ClinVar: Oct 14, 2018 Last updated: Oct 14, 2018 |
Comment:
The c.328T>A (p.Phe110Ile) variant has not been observed in general population but reported with high prevalence and segregation pattern in multiple hypertrophic cardiomyopathy (HCM) patients … (more)
The c.328T>A (p.Phe110Ile) variant has not been observed in general population but reported with high prevalence and segregation pattern in multiple hypertrophic cardiomyopathy (HCM) patients (PMID: 7898523, 9714088). It is well conversed during evolution and predicted to be deleterious by multiple in silica prediction software. This variant has been showed to dramatically increase Ca2+ sensitivity of force development in cardiac muscle preparation (PMID: 10617660). It has been also observed in other clinical labs and reported as pathogenic. At the same amino acid position, Phe110Ile (c.330T>G), Phe110Val, Phe110L are reported as deleterious variants. Based on the above evidences, we interpret this variant as pathogenic. (less)
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Pathogenic
(May 15, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003934662.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: TNNT2 c.328T>A (p.Phe110Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: TNNT2 c.328T>A (p.Phe110Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251494 control chromosomes. c.328T>A has been reported in the literature in multiple individuals affected with HCM, including families with segregation data (eg. Anan_1998, Lin_2000, etc). These data indicate that the variant is very likely to be associated with disease. Skinned papillary muscle fibers from transgenic mice expressing F110I and F110I-reconstituted human cardiac muscle preparations demonstrated increased Ca2 sensitivity of force and ATPase activity and impaired ATPase activation (Hernandez_2005, Szczesna_2000). Two 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
(Mar 04, 2021)
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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: SCV002053515.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
This missense variant replaces phenylalanine with isoleucine 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 isoleucine at codon 110 in the tropomyosin binding domain 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). A functional study has shown the mutant protein to exhibit increased Ca2+ sensitivity of force development and impaired ATPase activation in cardiac muscle preparation (PMID: 10617660). This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 7898523, 9482583, 9714088, 22112859, 23494605, 9714088) and has shown strong segregate with disease in six families, where the variant was associated with variable cardiac morphologies and a favorable prognosis (PMID: 9714088). This variant has not been identified 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
(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: SCV004181445.1
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: SCV004181446.1
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
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Genome-Nilou Lab
Accession: SCV004181447.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Jan 30, 2013)
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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: SCV000280521.1
First in ClinVar: Jun 03, 2016 Last updated: Jun 03, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. TNNT2 variant Phe110Ile (F110I; c.340T>A at the nucleotide level) The variant has been reported in at least 14 unrelated cases of HCM, and has segregated with disease in all affected family members tested (from 8 families). This includes strong segregation data from one Japanese family, and good segregation data from at least 3 others—plus extensive in vitro functional data and a Phe110Ile transgenic mouse model prone to arrhythmias. Cases: Watkins et al. (1995) first reported this variant in a proband with HCM, accompanied by weak segregation data: The variant was also present in the only other affected member of the family. Koga et al. (1996) detected it in 2 different Japanese 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. Anan et al. (1998) identified 6 different Japanese HCM families with the Phe110Ile variant. In 4 families, segregation analysis was possible. The variant segregated with disease in the following number of family members in each family: 3 (max separation: 2nd degree); 3 (max separation: 1st degree); 4 (max separation: 2nd degree); 3 (max separation: 2nd degree). Lin et al. (2000) reported Phe110Ile variants in a large Japanese HCM family, associated with significant biventricular hypertrophy and a high incidence of sudden death. Phe110Ile segregated with disease in all 6 affected individuals, 2 of whom were severely-affected homozygotes. The most distantly-related affected carriers of the variant were 3rd degree relatives (cousins). One family member died suddenly at age 18 while running and could not be genotyped. Konno et al. (2003, 2005) reported Phe110Ile in 2 Japanese individuals (it is not clear if they are related). Otsuka et al. (2011) found the variant in two unrelated Japanese probands, and in a third unrelated Japanese proband who also carried a TNNT2 Pro80Ser variant inherited from the other parent. Transgenic mice expressing Phe110Ile did not develop significant cardiac hypertrophy or fibrosis, but the variant impaired acute exercise tolerance; muscle fibers containing the variant had increased calcium sensitivity of force and an increased “energy cost” (ratio of ATPase/force) compared to wildtype (Hernandez 2005). Baudenbacher et al. (2008) showed the variant created arrhythmia (VT) susceptibility in transgenic mice. Other changes at codon 110 have also been associated with disease: Phe110Leu (we classify as likely disease causing) and Phe110Val (we classify as of uncertain significance, probably disease causing). Variation at nearby loci of TNNT2 (within 10 amino acids to either side) has been associated with disease, supporting the functional importance of this region of the protein. This includes Ala104Val (HCM) and Arg113Trp (DCM) (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 is available for the Phe110Ile variant specifically: Yanaga et al. (1999) showed the variant to potentiate the maximum level of ATPase activity in cardiac myofibrils. Nakaura et al. (1999) showed it to increase maximum contractile activity of skinned cardiac muscle fibers. Szczesna et al. (2000) showed it increased calcium sensitivity of force development in skinned cardiac muscle preparations, and troponin complexes containing the variant had impaired activation of myosin-ATPase. Takahashi-Yanaga et al. (2001) showed Phe110Ile to impair multiple calcium-regulating functions of troponin: It impaired the inhibitory function of troponin I, enhanced the neutralizing function of troponin C, and potentiated the maximum ATPase activity of myofibrils. Data from Palm et al. (2001) suggests that the Phe110Ile variant impairs binding of troponin T to tropomyosin, and makes the protein less effective at promoting the binding of tropomyosin to actin. Hinkle & Tobacman (2003) also showed Phe110Ile to significantly weaken binding of troponin to actin-tropomyosin. This is a conservative amino acid change from a nonpolar Phenylalanine to a nonpolar Isoleucine (with a smaller side-chain). The Phenylalanine at codon 110 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”. The Phe110Ile variant is listed in dbSNP as rs121964858 and labeled “probable-pathogenic”, as submitted by OMIM staff at Johns Hopkins. Controls: In total the variant has not been seen in ~5760 published controls and publicly available population datasets. Given the majority of reported cases are Japanese, it is important to note that the variant was not observed in a total of 360 Japanese controls. There is no variation at codon 110 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: Watkins et al. (1995) did not observe the variant in more than 100 control individuals, ethnicity not specified. Koga et al. (1996) did not detect the variant in more than 100 Japanese controls. Anan et al. (1998) did not detect it in 50 Japanese controls. Lin et al. (2000) did not observe it in 10 Japanese controls. Otsuka et al. (2011) did not observe it in 200 Japanese controls. (less)
Number of individuals with the variant: 10
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Pathogenic
(Aug 04, 1998)
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no assertion criteria provided
Method: literature only
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CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033470.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
In 2 affected members of a family with hypertrophic cardiomyopathy (CMH2; 115195), Watkins et al. (1995) identified a missense 340T-A transversion in the TNNT2 gene, … (more)
In 2 affected members of a family with hypertrophic cardiomyopathy (CMH2; 115195), Watkins et al. (1995) identified a missense 340T-A transversion in the TNNT2 gene, resulting in a phe110-to-ile (F110I) substitution. Anan et al. (1998) found the same mutation in 6 of 46 unrelated Japanese probands with familial CMH. Haplotype analysis supported a founder effect in 2 families, whereas the others had independent mutations. The authors suggested that residue 340 in the TNNT2 gene may represent a mutation hotspot. There was considerable inter- and intra-familial phenotypic variability, with apical hypertrophy alone in 2 unrelated families. In contrast to other reported TNNT2 mutations, F110I appeared to show a favorable prognosis, with Kaplan-Meier product-limit survival curves similar to those seen in patients with phe513-to-cys beta-myosin heavy chain mutations (160760.0016). (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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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 |
Phenotypic variation of familial hypertrophic cardiomyopathy caused by the Phe(110)-->Ile mutation in cardiac troponin T. | Lin T | Cardiology | 2000 | PMID: 10965086 |
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 |
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 |
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 |
Text-mined citations for rs121964858 ...
HelpRecord last updated Dec 30, 2023
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.