ClinVar Genomic variation as it relates to human health
NM_006757.4(TNNT3):c.188G>A (p.Arg63His)
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_006757.4(TNNT3):c.188G>A (p.Arg63His)
Variation ID: 8913 Accession: VCV000008913.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 1933737 (GRCh38) [ NCBI UCSC ] 11: 1954967 (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 May 19, 2024 Aug 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006757.4:c.188G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006748.1:p.Arg63His missense NM_001042780.3:c.164G>A NP_001036245.1:p.Arg55His missense NM_001042781.3:c.182G>A NP_001036246.1:p.Arg61His missense NM_001042782.3:c.164G>A NP_001036247.1:p.Arg55His missense NM_001297646.2:c.164G>A NP_001284575.1:p.Arg55His missense NM_001363561.2:c.197G>A NP_001350490.1:p.Arg66His missense NM_001367842.1:c.182G>A NP_001354771.1:p.Arg61His missense NM_001367843.1:c.182G>A NP_001354772.1:p.Arg61His missense NM_001367844.1:c.164G>A NP_001354773.1:p.Arg55His missense NM_001367845.1:c.164G>A NP_001354774.1:p.Arg55His missense NM_001367846.1:c.221G>A NP_001354775.1:p.Arg74His missense NM_001367847.1:c.197G>A NP_001354776.1:p.Arg66His missense NM_001367848.1:c.185G>A NP_001354777.1:p.Arg62His missense NM_001367849.1:c.176G>A NP_001354778.1:p.Arg59His missense NM_001367850.1:c.131G>A NP_001354779.1:p.Arg44His missense NM_001367851.1:c.-17G>A 5 prime UTR NM_001367852.1:c.-17G>A 5 prime UTR NC_000011.10:g.1933737G>A NC_000011.9:g.1954967G>A LRG_850t1:c.188G>A LRG_850p1:p.Arg63His - Protein change
- R63H, R59H, R61H, R66H, R44H, R55H, R62H, R74H
- Other names
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- Canonical SPDI
- NC_000011.10:1933736:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- functional variant Sequence Ontology [SO:0001536]
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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
Help
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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TNNT3 | - | - |
GRCh38 GRCh38 GRCh37 |
244 | 284 |
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
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
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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/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Aug 23, 2023 | RCV000009468.14 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Nov 30, 2021 | RCV000024561.27 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 5, 2015 | RCV000194919.9 |
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
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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
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
(Mar 05, 2015)
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criteria provided, single submitter
Method: clinical testing
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Arthyrgryposis, distal, type 2B
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000249171.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(Aug 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Arthrogryposis, distal, type 2B2
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004039193.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: TNNT3 c.188G>A (p.Arg63His) results in a non-conservative amino acid change in the encoded protein sequence, altering a highly conserved residue (HGMD) in which … (more)
Variant summary: TNNT3 c.188G>A (p.Arg63His) results in a non-conservative amino acid change in the encoded protein sequence, altering a highly conserved residue (HGMD) in which two other missense variants (p.Arg63Cys, p.Arg63Ser) have been classified as pathogenic or likely pathogenic by ClinVar submitters. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249900 control chromosomes (gnomAD). c.188G>A has been reported in the literature in multiple individuals affected with distal arthrogryposis type 1 and 2b (Sung_2003, Gurnett_2009, Laquerriere_2014, Vora_2020). The variant was reported as a de novo occurrence in some of these cases, as well as in an internal case with features suggestive of possible arthrogryposis. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 19142688, 12865991, 24319099, 31974414). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248092.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 2
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Pathogenic
(Dec 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Arthrogryposis, distal, type 2B2
Affected status: yes
Allele origin:
de novo
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New York Genome Center
Study: PrenatalSEQ
Accession: SCV005044176.1 First in ClinVar: May 19, 2024 Last updated: May 19, 2024 |
Comment:
The de novo heterozygous c.188G>A, p.(Arg63His) variant identified in the TNNT3 gene substitutes a well conserved Arginine for Histidine at amino acid 63/259 (exon 10/16). … (more)
The de novo heterozygous c.188G>A, p.(Arg63His) variant identified in the TNNT3 gene substitutes a well conserved Arginine for Histidine at amino acid 63/259 (exon 10/16). This variant is absent from population databases (gnomADv2.1.1, gnomADv3.1.2, BRAVO-TOPMed, All of Us) suggesting it is not a common benign variant in the populations represented in those databases. In silico algorithms predict this variant to be damaging to the canonical transcript (REVEL; score=0.959). This variant is reported as Pathogenic in ClinVar (VarID:8913, 9 submissions, no conflicts), and a different amino acid change at the same amino acid, p.Arg63Cys is also classified as Pathogenic (VarID:31874). The c.188G>A, p.(Arg63His) variant identified in this fetus has been reported in many affected individuals in the literature [PMID:25337069, 32779773, 31974414, 23401156, 12865991] and functional studies suggest that the p.Arg63His variant significantly enhances ATPase activity and increases calcium sensitivity [PMID:17194691]. Given its absence in population databases, observation in many affected individuals, functional studies, and presence de novo here, the heterozygous c.188G>A, p.(Arg63His) variant identified in the TNNT3 gene is reported as Pathogenic (less)
Clinical Features:
Congenital vertical talus (present) , Hand clenching (present)
Age: 30-39 weeks gestation
Secondary finding: no
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Pathogenic
(Aug 22, 2019)
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criteria provided, single submitter
Method: curation
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Arthrogryposis, distal, type 2B2
Affected status: unknown
Allele origin:
unknown
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SIB Swiss Institute of Bioinformatics
Accession: SCV000996473.1
First in ClinVar: Nov 02, 2019 Last updated: Nov 02, 2019 |
Comment:
This variant is interpreted as a Pathogenic for Arthrogryposis, distal, 2B2, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PM6, PP3, PP1-Strong, PS4-Supporting.
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Pathogenic
(Feb 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Arthrogryposis, distal, type 2B2
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581394.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PS4, PP1, PP3
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Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Nov 28, 2021)
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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: SCV000516047.7
First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023 |
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is … (more)
Not observed in large population cohorts (gnomAD); 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: 19142688, 23401156, 24319099, 12865991, 25337069, 30216196, 31974414, 32779773, 26915936) (less)
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Pathogenic
(Nov 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV004026477.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
PP3, PM5, PP4, PS4, PM2_SUP, PP1
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: not provided
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Arthrogryposis, distal, type 2B2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University Hospital of Duesseldorf
Accession: SCV004171133.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
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Pathogenic
(May 01, 2009)
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no assertion criteria provided
Method: literature only
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ARTHROGRYPOSIS, DISTAL, TYPE 2B2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000029686.3
First in ClinVar: Apr 04, 2013 Last updated: May 20, 2019 |
Comment on evidence:
In a woman with distal arthrogryposis multiplex congenita type 2B2 (DA2B2; 618435) and her 2 affected daughters, Sung et al. (2003) identified a c.188G-A transition … (more)
In a woman with distal arthrogryposis multiplex congenita type 2B2 (DA2B2; 618435) and her 2 affected daughters, Sung et al. (2003) identified a c.188G-A transition (c.188G-A, NM_006757) in exon 9 of the TNNT3 cDNA, resulting in an arg63-to-his (R63H) substitution. The mutation was thought to be disease-causing for several reasons: it was identified in the proband and was also present in all affected family members; it was not found in 488 chromosomes from an ethnically matched control group; it results in the substitution of an amino acid residue that is conserved in all isoforms of troponin T (TnT), implying that this difference is likely to have structural and/or functional consequences; and Varnava et al. (1999) found that substitution of the homologous amino acid residue in the cardiac-specific form of TnT (TNNT2; 191045) causes cardiomyopathy. Gurnett et al. (2009) identified the R63H mutation as a de novo occurrence in an infant with 4-extremity arthrogryposis but no facial involvement. The authors noted that it is admittedly difficult to diagnose mild forms of facial weakness, particularly in infancy, although they classified the disorder in this child as distal arthrogryposis-1 (108120). In affected members of a 4-generation Indian family segregating distal arthrogryposis, Daly et al. (2014) identified heterozygosity for the R63H mutation in the TNNT3 gene. The mutation, which was found by exome sequencing, was confirmed by Sanger sequencing. Daly et al. (2014) classified the phenotype in the family as 'DA1 or a milder variant of DA2B.' (less)
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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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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001918658.1 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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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001974103.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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not provided
(Mar 18, 2012)
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no classification provided
Method: curation
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not specified
Affected status: not provided
Allele origin:
germline,
de novo
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Leiden Muscular Dystrophy (TNNT3)
Accession: SCV000045865.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Observation 1: Observation 2: |
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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has functional consequence
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Leiden Muscular Dystrophy (TNNT3)
Accession: SCV000045865.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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An approach to integrating exome sequencing for fetal structural anomalies into clinical practice. | Vora NL | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31974414 |
Exome Sequencing Identifies a Dominant TNNT3 Mutation in a Large Family with Distal Arthrogryposis. | Daly SB | Molecular syndromology | 2014 | PMID: 25337069 |
Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects. | Laquérriere A | Human molecular genetics | 2014 | PMID: 24319099 |
Skeletal muscle contractile gene (TNNT3, MYH3, TPM2) mutations not found in vertical talus or clubfoot. | Gurnett CA | Clinical orthopaedics and related research | 2009 | PMID: 19142688 |
Mutations in TNNT3 cause multiple congenital contractures: a second locus for distal arthrogryposis type 2B. | Sung SS | American journal of human genetics | 2003 | PMID: 12865991 |
A new mutation of the cardiac troponin T gene causing familial hypertrophic cardiomyopathy without left ventricular hypertrophy. | Varnava A | Heart (British Cardiac Society) | 1999 | PMID: 10525521 |
Text-mined citations for rs121434638 ...
HelpRecord last updated May 19, 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.