Published functional studies suggest a damaging effect during activation as the variant partially inhibits both calcium- and myosin-induced tropomyosin movement over the thin filament (Ochala et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); 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: 26307083, 22519952, 23401156, 18422639, 24692096, 23678273, 17339586, 17430991, 31526942, 32092148, 30199282, 31535252, 31864708, 32528171, 20457903, 35579956, 33066566, Neissi2022[Case Report])
ClinVar Genomic variation as it relates to human health
NM_003289.4(TPM2):c.397C>T (p.Arg133Trp)
Germline
Classification
Help
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.
(9)
Help
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
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003289.4(TPM2):c.397C>T (p.Arg133Trp)
Variation ID: 12463 Accession: VCV000012463.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p13.3 9: 35685529 (GRCh38) [ NCBI UCSC ] 9: 35685526 (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 Oct 8, 2024 Jun 30, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003289.4:c.397C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003280.2:p.Arg133Trp missense NM_001301226.2:c.397C>T NP_001288155.1:p.Arg133Trp missense NM_001301227.1:c.397C>T NM_001301227.2:c.397C>T NP_001288156.1:p.Arg133Trp missense NM_213674.1:c.397C>T NP_998839.1:p.Arg133Trp missense NC_000009.12:g.35685529G>A NC_000009.11:g.35685526G>A NG_011620.1:g.9529C>T LRG_680:g.9529C>T LRG_680t1:c.397C>T LRG_680p1:p.Arg133Trp LRG_680t2:c.397C>T LRG_680p2:p.Arg133Trp P07951:p.Arg133Trp - Protein change
- R133W
- Other names
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- Canonical SPDI
- NC_000009.12:35685528:G:A
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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.
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- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
| TPM2 | - | - |
GRCh38 GRCh37 |
309 | 387 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
May 1, 2013 | RCV000013279.26 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jun 30, 2022 | RCV000128682.7 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Nov 5, 2021 | RCV001775067.9 | |
|
TPM2-related disorder
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Pathogenic (1) |
no assertion criteria provided
|
Nov 28, 2023 | RCV004532331.3 |
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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|---|---|---|---|---|---|
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Pathogenic
(Jun 06, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Arthrogryposis, distal, type 1A
Affected status: yes
Allele origin:
de novo
|
Centogene AG - the Rare Disease Company
Accession: SCV002059843.1
First in ClinVar: Jan 14, 2022 Last updated: Jan 14, 2022 |
|
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Pathogenic
(Jun 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002546623.2
First in ClinVar: Jul 17, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies suggest a damaging effect during activation as the variant partially inhibits both calcium- and myosin-induced tropomyosin movement over the thin filament (Ochala … (more)
Published functional studies suggest a damaging effect during activation as the variant partially inhibits both calcium- and myosin-induced tropomyosin movement over the thin filament (Ochala et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); 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: 26307083, 22519952, 23401156, 18422639, 24692096, 23678273, 17339586, 17430991, 31526942, 32092148, 30199282, 31535252, 31864708, 32528171, 20457903, 35579956, 33066566, Neissi2022[Case Report]) (less)
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Pathogenic
(Jan 09, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000859087.1
First in ClinVar: Jul 23, 2014 Last updated: Jul 23, 2014 |
Number of individuals with the variant: 1
Sex: mixed
|
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Pathogenic
(Oct 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Arthrogryposis, distal, type 1A
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002012084.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 23678273,17339586, PS1_S). The variant was … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 23678273,17339586, PS1_S). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2).In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.788, 3Cnet: 0.871, PP3). Patient's phenotype is considered compatible with Arthrogryposis, distal, (3billion dataset, PP4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Arthrogryposis multiplex congenita (present) , Clubfoot (present) , Limited mobility of proximal interphalangeal joint (present)
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Pathogenic
(Nov 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Arthrogryposis, distal, type 1A
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002235791.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg133 amino acid residue in TPM2. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg133 amino acid residue in TPM2. Other variant(s) that disrupt this residue have been observed in individuals with TPM2-related conditions (PMID: 24692096), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 12463). This missense change has been observed in individuals with arthrogryposis and/or congenital myopathy (PMID: 17339586, 23678273, 24692096, 32092148). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 133 of the TPM2 protein (p.Arg133Trp). (less)
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Arthrogryposis, distal, type 1A
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Suma Genomics
Accession: SCV004849373.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
|
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Pathogenic
(May 01, 2013)
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no assertion criteria provided
Method: literature only
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ARTHROGRYPOSIS, DISTAL, TYPE 2B4
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033526.4
First in ClinVar: Apr 04, 2013 Last updated: May 20, 2019 |
Comment on evidence:
In a mother and daughter with a form of distal arthrogryposis most consistent with type 2B (DA2B4; see 108120), Tajsharghi et al. (2007) identified a … (more)
In a mother and daughter with a form of distal arthrogryposis most consistent with type 2B (DA2B4; see 108120), Tajsharghi et al. (2007) identified a heterozygous 5396C-T transition in exon 4 of the TPM2 gene, resulting in an arg133-to-trp (R133W) substitution. At the time of the report, the mother and daughter were 65 and 28 years, respectively. Both had presented with distal joint contractures at birth. At the time of examination, both complained of muscle weakness in proximal and distal muscles, most prominent in the hands and feet. Other notable features in both patients included hearing impairment, high-arched palate, short neck, short stature, contractures in proximal joints, smooth palms, and scoliosis. Neither had cardiac involvement. In a Korean mother and daughter with DA2B4, Ko et al. (2013) identified heterozygosity for the R133W mutation in the TPM2 gene. (less)
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Pathogenic
(Nov 28, 2023)
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no assertion criteria provided
Method: clinical testing
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TPM2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004750518.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The TPM2 c.397C>T variant is predicted to result in the amino acid substitution p.Arg133Trp. This variant has been reported in many unrelated individuals to be … (more)
The TPM2 c.397C>T variant is predicted to result in the amino acid substitution p.Arg133Trp. This variant has been reported in many unrelated individuals to be causative for TPM2-related disorders (Ochala et al. 2007. PubMed ID 17430991; Marttila et al. 2014. PubMed ID: 24692096; Beck et al. 2013. PubMed ID: 23401156; Table S4, Töpf et al. 2020. PubMed ID: 32528171; Vogt et al. 2020. PubMed ID: 32092148). Functional studies suggested that this variant leads to disrupted regulation of muscle contraction (Ochala et al. 2007. PubMed ID: 17430991). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/12463/). This variant is interpreted as pathogenic. (less)
|
|
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not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
de novo,
germline
|
TPM2 homepage - Leiden Muscular Dystrophy pages
Accession: SCV000172322.1
First in ClinVar: Jul 23, 2014 Last updated: Jul 23, 2014 |
Observation 1: Observation 2: |
Comment:
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 23678273,17339586, PS1_S). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2).In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.788, 3Cnet: 0.871, PP3). Patient's phenotype is considered compatible with Arthrogryposis, distal, (3billion dataset, PP4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg133 amino acid residue in TPM2. Other variant(s) that disrupt this residue have been observed in individuals with TPM2-related conditions (PMID: 24692096), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 12463). This missense change has been observed in individuals with arthrogryposis and/or congenital myopathy (PMID: 17339586, 23678273, 24692096, 32092148). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 133 of the TPM2 protein (p.Arg133Trp).
Comment:
The TPM2 c.397C>T variant is predicted to result in the amino acid substitution p.Arg133Trp. This variant has been reported in many unrelated individuals to be causative for TPM2-related disorders (Ochala et al. 2007. PubMed ID 17430991; Marttila et al. 2014. PubMed ID: 24692096; Beck et al. 2013. PubMed ID: 23401156; Table S4, Töpf et al. 2020. PubMed ID: 32528171; Vogt et al. 2020. PubMed ID: 32092148). Functional studies suggested that this variant leads to disrupted regulation of muscle contraction (Ochala et al. 2007. PubMed ID: 17430991). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/12463/). This variant is interpreted as pathogenic.
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. |
Comment:
Published functional studies suggest a damaging effect during activation as the variant partially inhibits both calcium- and myosin-induced tropomyosin movement over the thin filament (Ochala et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); 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: 26307083, 22519952, 23401156, 18422639, 24692096, 23678273, 17339586, 17430991, 31526942, 32092148, 30199282, 31535252, 31864708, 32528171, 20457903, 35579956, 33066566, Neissi2022[Case Report])
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 23678273,17339586, PS1_S). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2).In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.788, 3Cnet: 0.871, PP3). Patient's phenotype is considered compatible with Arthrogryposis, distal, (3billion dataset, PP4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg133 amino acid residue in TPM2. Other variant(s) that disrupt this residue have been observed in individuals with TPM2-related conditions (PMID: 24692096), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 12463). This missense change has been observed in individuals with arthrogryposis and/or congenital myopathy (PMID: 17339586, 23678273, 24692096, 32092148). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 133 of the TPM2 protein (p.Arg133Trp).
Comment:
The TPM2 c.397C>T variant is predicted to result in the amino acid substitution p.Arg133Trp. This variant has been reported in many unrelated individuals to be causative for TPM2-related disorders (Ochala et al. 2007. PubMed ID 17430991; Marttila et al. 2014. PubMed ID: 24692096; Beck et al. 2013. PubMed ID: 23401156; Table S4, Töpf et al. 2020. PubMed ID: 32528171; Vogt et al. 2020. PubMed ID: 32092148). Functional studies suggested that this variant leads to disrupted regulation of muscle contraction (Ochala et al. 2007. PubMed ID: 17430991). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/12463/). This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A recurrent pathogenic variant in TPM2 reveals further phenotypic and genetic heterogeneity in multiple pterygium syndrome-related disorders. | Vogt J | Clinical genetics | 2020 | PMID: 32092148 |
| Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. | Zhang W | Human mutation | 2018 | PMID: 29068549 |
| Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing congenital myopathies. | Marttila M | Human mutation | 2014 | PMID: 24692096 |
| First Korean family with a mutation in TPM2 associated with Sheldon-Hall syndrome. | Ko JM | Journal of Korean medical science | 2013 | PMID: 23678273 |
| Distal arthrogryposis and muscle weakness associated with a beta-tropomyosin mutation. | Tajsharghi H | Neurology | 2007 | PMID: 17339586 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TPM2 | - | - | - | - |
Text-mined citations for rs137853305 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 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.