ClinVar Genomic variation as it relates to human health
NM_003282.4(TNNI2):c.466C>T (p.Arg156Ter)
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_003282.4(TNNI2):c.466C>T (p.Arg156Ter)
Variation ID: 12436 Accession: VCV000012436.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 1841468 (GRCh38) [ NCBI UCSC ] 11: 1862698 (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 Jul 23, 2014 Feb 20, 2024 Sep 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003282.4:c.466C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003273.1:p.Arg156Ter nonsense NM_001145829.2:c.466C>T NP_001139301.1:p.Arg156Ter nonsense NM_001145841.2:c.466C>T NP_001139313.1:p.Arg156Ter nonsense NC_000011.10:g.1841468C>T NC_000011.9:g.1862698C>T NG_011621.1:g.7466C>T LRG_851:g.7466C>T LRG_851t1:c.466C>T LRG_851p1:p.Arg156Ter - Protein change
- R156*
- Other names
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- Canonical SPDI
- NC_000011.10:1841467: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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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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TNNI2 | - | - |
GRCh38 GRCh38 GRCh37 |
94 | 134 |
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 (3) |
criteria provided, multiple submitters, no conflicts
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Sep 23, 2022 | RCV000128665.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 6, 2014 | RCV000415208.5 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Sep 8, 2023 | RCV000013249.28 |
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 25, 2015)
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criteria provided, single submitter
Method: clinical testing
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Arthrogryposis multiplex congenita, distal, type 2B
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000597509.1
First in ClinVar: Jun 02, 2016 Last updated: Jun 02, 2016 |
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Pathogenic
(Mar 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Distal arthrogryposis type 2B1
Affected status: yes
Allele origin:
germline
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Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust
Accession: SCV003853397.1
First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
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Pathogenic
(Sep 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Distal arthrogryposis type 2B1
Affected status: yes
Allele origin:
de novo
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Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine
Accession: SCV004543814.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Sex: female
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Pathogenic
(Mar 06, 2014)
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criteria provided, single submitter
Method: clinical testing
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Calcaneovalgus deformity
Congenital finger flexion contractures Distal arthrogryposis Ulnar deviation of the wrist
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000493003.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
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Pathogenic
(Apr 09, 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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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449715.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 2
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Pathogenic
(Sep 06, 2019)
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criteria provided, single submitter
Method: clinical testing
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Distal arthrogryposis type 2B1
Affected status: yes
Allele origin:
de novo
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Baylor Genetics
Accession: SCV001521178.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic in multiple patients with … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic in multiple patients with type 2B distal arthrogryposis [PMID 12592607, 17101001, 17194691, ClinVar ID: 12436] (less)
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Pathogenic
(Dec 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Distal arthrogryposis type 2B1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV002759358.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Clinical Features:
Distal arthrogryposis (present)
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Pathogenic
(Sep 23, 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: SCV001792921.3
First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed in … (more)
Nonsense variant predicted to result in protein truncation, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18331830, 21402185, 17101001, 25340332, 16497570, 16802141, 23401156, 12592607, 17194691, 33726816, 33060286) (less)
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Pathogenic
(Dec 01, 2006)
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no assertion criteria provided
Method: literature only
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ARTHROGRYPOSIS, DISTAL, TYPE 2B1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033496.3
First in ClinVar: Apr 04, 2013 Last updated: May 27, 2019 |
Comment on evidence:
In 2 unrelated families, Sung et al. (2003) found that type 2B distal arthrogryposis (DA2B1; 601680) was caused by a 466C-T transition in exon 8 … (more)
In 2 unrelated families, Sung et al. (2003) found that type 2B distal arthrogryposis (DA2B1; 601680) was caused by a 466C-T transition in exon 8 of the TNNI2 gene, resulting in a mutant TnI lacking 26 amino acid residues at the carboxy terminus (arg156-to-ter; R156X). In 1 kindred this mutation arose de novo in the affected father and was subsequently transmitted to all of his offspring, each of whom was affected and had a different mother. The segregation of the mutation in the second kindred suggested either that it arose de novo twice or that mosaicism for this mutation existed in 1 of the phenotypically normal parents. However, the level of mosaicism may have been too low to be detected in lymphocytes and/or may have existed in cell populations that were not tested (e.g., gonadal tissue). Drera et al. (2006) identified a heterozygous R156X mutation in an Italian mother and son with DA2B1. The authors noted that the C terminus of TnI plays a role in conferring Ca(2+) sensitivity and actin affinity, suggesting that the mutant protein lacks the ability to inhibit muscle contraction in the absence of Ca(2+). (less)
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
germline,
somatic
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TNNI2 homepage - Leiden Muscular Dystrophy pages
Accession: SCV000172305.1
First in ClinVar: Jul 23, 2014 Last updated: Jul 23, 2014
Comment:
has functional consequence
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Observation 1: Observation 2: |
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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Mutations in fast skeletal troponin I, troponin T, and beta-tropomyosin that cause distal arthrogryposis all increase contractile function. | Robinson P | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 2007 | PMID: 17194691 |
Recurrence of the p.R156X TNNI2 mutation in distal arthrogryposis type 2B. | Drera B | Clinical genetics | 2006 | PMID: 17101001 |
Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes. | Sung SS | American journal of human genetics | 2003 | PMID: 12592607 |
Text-mined citations for rs104894312 ...
HelpRecord last updated May 08, 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.