Variant summary: TPM2 c.415_417delGAG (p.Glu139del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 251480 control chromosomes. c.415_417delGAG has been reported in the literature in multiple individuals affected with Nemaline Myopathy 4 (Cap myopathy) (example, Lehtokari_2007, Clarke_2009, Tasca_2013, Citirak_2014). Some of the ascertained reports indicated a de-novo origin and at-least once instance of somatic mosaicism resulting in a milder presentation has been reported (example, Tasca_2013). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence that the mutant protein incorporates into sarcomeric structures, where it likely imposes a dominant-negative effect to cause muscle weakness (example, Clarke_2009) and increased myofibrillar calcium sensitivity consistent with a gain of function mechanism (example, Marston_2013). 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.
ClinVar Genomic variation as it relates to human health
NM_003289.4(TPM2):c.412GAG[1] (p.Glu139del)
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.412GAG[1] (p.Glu139del)
Variation ID: 12465 Accession: VCV000012465.26
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 9p13.3 9: 35685509-35685511 (GRCh38) [ NCBI UCSC ] 9: 35685506-35685508 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Dec 22, 2024 Mar 6, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003289.4:c.412GAG[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003280.2:p.Glu139del inframe deletion NM_003289.4:c.415_417del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001301226.2:c.412GAG[1] NP_001288155.1:p.Glu139del inframe deletion NM_001301227.2:c.412GAG[1] NP_001288156.1:p.Glu139del inframe deletion NM_003289.3:c.415_417delGAG NM_213674.1:c.412GAG[1] NP_998839.1:p.Glu139del inframe deletion NC_000009.12:g.35685509CTC[1] NC_000009.11:g.35685506CTC[1] NG_011620.1:g.9544GAG[1] LRG_680:g.9544GAG[1] LRG_680t1:c.412GAG[1] LRG_680p1:p.Glu139del - Protein change
- E139del
- Other names
- -
- Canonical SPDI
- NC_000009.12:35685508:CTCCTC:CTC
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
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 |
310 | 388 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 6, 2024 | RCV000500415.19 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 4, 2020 | RCV000532873.13 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Feb 1, 2023 | RCV000128684.21 | |
|
TPM2-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Feb 15, 2024 | RCV004528107.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Apr 28, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Nemaline myopathy 4
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000597527.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
|
|
|
Pathogenic
(Apr 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myopathy 23
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002511663.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
Variant summary: TPM2 c.415_417delGAG (p.Glu139del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was … (more)
Variant summary: TPM2 c.415_417delGAG (p.Glu139del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 251480 control chromosomes. c.415_417delGAG has been reported in the literature in multiple individuals affected with Nemaline Myopathy 4 (Cap myopathy) (example, Lehtokari_2007, Clarke_2009, Tasca_2013, Citirak_2014). Some of the ascertained reports indicated a de-novo origin and at-least once instance of somatic mosaicism resulting in a milder presentation has been reported (example, Tasca_2013). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence that the mutant protein incorporates into sarcomeric structures, where it likely imposes a dominant-negative effect to cause muscle weakness (example, Clarke_2009) and increased myofibrillar calcium sensitivity consistent with a gain of function mechanism (example, Marston_2013). 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)
|
|
|
Pathogenic
(Mar 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myopathy 23
Affected status: yes
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005091070.1
First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 |
Comment:
PS3, PM1, PM2, PM4, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 12465). This variant has been … (more)
PS3, PM1, PM2, PM4, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 12465). This variant has been previously reported as causative for congenital myopathy (PMID:24507666). (less)
|
|
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Pathogenic
(Nov 04, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myopathy 23
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002581247.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PS4_MOD, PM4, PM6, PM2_SUP
|
Number of individuals with the variant: 1
Sex: female
|
|
|
Pathogenic
(Mar 04, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Arthrogryposis, distal, type 1A
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000630170.4
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this in-frame deletion causes increased calcium sensitivity and inhibits myosin … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this in-frame deletion causes increased calcium sensitivity and inhibits myosin binding (PMID: 23886664, 25978979). This variant has been reported in multiple unrelated individuals affected with autosomal dominant cap myopathy and nemaline myopathy (PMID: 17434307, 23015096, 24692096, 25127990), including several affected individuals where it arose de novo (PMID: 19345583, 24507666). ClinVar contains an entry for this variant (Variation ID: 12465). This variant is not present in population databases (ExAC no frequency). This variant, c.415_417del, results in the deletion of 1 amino acid of the TPM2 protein (p.Glu139del), but otherwise preserves the integrity of the reading frame. (less)
|
|
|
Pathogenic
(Feb 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV003917658.14
First in ClinVar: Apr 23, 2023 Last updated: Dec 22, 2024 |
Comment:
TPM2: PS2, PM2, PS3:Moderate, PS4:Moderate
Number of individuals with the variant: 1
|
|
|
Pathogenic
(May 01, 2009)
|
no assertion criteria provided
Method: literature only
|
CONGENITAL MYOPATHY 23
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033528.5
First in ClinVar: Apr 04, 2013 Last updated: Jul 23, 2024 |
Comment on evidence:
In a 36-year-old man with congenital myopathy-23 (CMYO23; 609285) since childhood, Lehtokari et al. (2007) identified a heterozygous 3-bp in-frame deletion (c.415delGAG, ENST00000329305) in exon … (more)
In a 36-year-old man with congenital myopathy-23 (CMYO23; 609285) since childhood, Lehtokari et al. (2007) identified a heterozygous 3-bp in-frame deletion (c.415delGAG, ENST00000329305) in exon 4 of the TPM2 gene, resulting in the removal of glu139 and predicted to disrupt the 7-amino acid repeat essential for making a coiled-coil motif and to impair tropomyosin-actin interaction. The patient had delayed motor development, was never able to run, showed generalized muscle weakness, and had additional features, including hyperlordosis, ptosis, and high-arched palate. Clarke et al. (2009) reported a 14-year-old Australian girl with CMYO23 who was heterozygous for the 415delGAG deletion (c.415delGAG, NM_003289). She had a history of hypotonia since infancy, delayed motor development, and slow running. She had generalized muscle wasting and weakness, particularly in the proximal muscles, and hyporeflexia. Other features included mild facial weakness, nasal voice, high-arched palate, long thin face, and mild micrognathia. Cardiac examination showed decreased systolic function, with an ejection fraction of 42%, mild mitral valve prolapse, and borderline aortic root dilatation. She also had central hypoventilation and restrictive lung disease with decreased forced vital capacity, and developed thoracic scoliosis in her teens. Skeletal muscle biopsy at age 10 showed fiber type variability, and she received an initial diagnosis of congenital fiber-type disproportion, a diagnosis of exclusion. However, about 4% of fibers were later noted to have caps, leading to a final histologic diagnosis of cap myopathy. There was type 1 fiber predominance. Electron microscopy showed irregular and thickened Z-lines, and the caps contained disorganized thin filaments. No classic nemaline rods were observed. Protein studies showed that the mutant TPM2 protein interacted with the wildtype protein and was incorporated into the sarcomere. The authors postulated that the mutation probably weakened the interaction with other proteins within skeletal muscle. Clarke et al. (2009) noted that the cardiac involvement in this patient was an unusual finding. (less)
|
|
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Pathogenic
(Feb 15, 2024)
|
no assertion criteria provided
Method: clinical testing
|
TPM2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004109058.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The TPM2 c.415_417delGAG variant is predicted to result in an in-frame deletion (p.Glu139del). This variant was reported in numerous individuals with nemaline myopathy or CAP … (more)
The TPM2 c.415_417delGAG variant is predicted to result in an in-frame deletion (p.Glu139del). This variant was reported in numerous individuals with nemaline myopathy or CAP myopathy (Lehtokari et al. 2007. PubMed ID: 17434307; Marttila et al. 2014. PubMed ID: 24692096; Table S1, Westra et al. 2019. PubMed ID: 31127727; Supplementary data, Gonzalez-Quereda et al. 2020. PubMed ID: 32403337). Functional studies showed that this variant impacts normal protein function (Marttila et al. 2012. PubMed ID: 22084935; Marston et al. 2013. PubMed ID: 23886664; Borovikov et al. 2015. PubMed ID: 25978979). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. (less)
|
|
|
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: SCV000172324.1
First in ClinVar: Jul 23, 2014 Last updated: Jul 23, 2014 |
Observation 1: Observation 2: |
Comment:
Comment:
PS3, PM1, PM2, PM4, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 12465). This variant has been previously reported as causative for congenital myopathy (PMID:24507666).
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this in-frame deletion causes increased calcium sensitivity and inhibits myosin binding (PMID: 23886664, 25978979). This variant has been reported in multiple unrelated individuals affected with autosomal dominant cap myopathy and nemaline myopathy (PMID: 17434307, 23015096, 24692096, 25127990), including several affected individuals where it arose de novo (PMID: 19345583, 24507666). ClinVar contains an entry for this variant (Variation ID: 12465). This variant is not present in population databases (ExAC no frequency). This variant, c.415_417del, results in the deletion of 1 amino acid of the TPM2 protein (p.Glu139del), but otherwise preserves the integrity of the reading frame.
Comment:
TPM2: PS2, PM2, PS3:Moderate, PS4:Moderate
Comment:
The TPM2 c.415_417delGAG variant is predicted to result in an in-frame deletion (p.Glu139del). This variant was reported in numerous individuals with nemaline myopathy or CAP myopathy (Lehtokari et al. 2007. PubMed ID: 17434307; Marttila et al. 2014. PubMed ID: 24692096; Table S1, Westra et al. 2019. PubMed ID: 31127727; Supplementary data, Gonzalez-Quereda et al. 2020. PubMed ID: 32403337). Functional studies showed that this variant impacts normal protein function (Marttila et al. 2012. PubMed ID: 22084935; Marston et al. 2013. PubMed ID: 23886664; Borovikov et al. 2015. PubMed ID: 25978979). This variant has not been reported in a large population database, indicating this variant is rare. 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:
Variant summary: TPM2 c.415_417delGAG (p.Glu139del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 251480 control chromosomes. c.415_417delGAG has been reported in the literature in multiple individuals affected with Nemaline Myopathy 4 (Cap myopathy) (example, Lehtokari_2007, Clarke_2009, Tasca_2013, Citirak_2014). Some of the ascertained reports indicated a de-novo origin and at-least once instance of somatic mosaicism resulting in a milder presentation has been reported (example, Tasca_2013). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence that the mutant protein incorporates into sarcomeric structures, where it likely imposes a dominant-negative effect to cause muscle weakness (example, Clarke_2009) and increased myofibrillar calcium sensitivity consistent with a gain of function mechanism (example, Marston_2013). 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.
Comment:
PS3, PM1, PM2, PM4, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 12465). This variant has been previously reported as causative for congenital myopathy (PMID:24507666).
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this in-frame deletion causes increased calcium sensitivity and inhibits myosin binding (PMID: 23886664, 25978979). This variant has been reported in multiple unrelated individuals affected with autosomal dominant cap myopathy and nemaline myopathy (PMID: 17434307, 23015096, 24692096, 25127990), including several affected individuals where it arose de novo (PMID: 19345583, 24507666). ClinVar contains an entry for this variant (Variation ID: 12465). This variant is not present in population databases (ExAC no frequency). This variant, c.415_417del, results in the deletion of 1 amino acid of the TPM2 protein (p.Glu139del), but otherwise preserves the integrity of the reading frame.
Comment:
TPM2: PS2, PM2, PS3:Moderate, PS4:Moderate
Comment:
The TPM2 c.415_417delGAG variant is predicted to result in an in-frame deletion (p.Glu139del). This variant was reported in numerous individuals with nemaline myopathy or CAP myopathy (Lehtokari et al. 2007. PubMed ID: 17434307; Marttila et al. 2014. PubMed ID: 24692096; Table S1, Westra et al. 2019. PubMed ID: 31127727; Supplementary data, Gonzalez-Quereda et al. 2020. PubMed ID: 32403337). Functional studies showed that this variant impacts normal protein function (Marttila et al. 2012. PubMed ID: 22084935; Marston et al. 2013. PubMed ID: 23886664; Borovikov et al. 2015. PubMed ID: 25978979). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Early-Onset Myopathies: Clinical Findings, Prevalence of Subgroups and Diagnostic Approach in a Single Neuromuscular Referral Center in Germany. | Vill K | Journal of neuromuscular diseases | 2017 | PMID: 29172004 |
| Aberrant movement of β-tropomyosin associated with congenital myopathy causes defective response of myosin heads and actin during the ATPase cycle. | Borovikov YS | Archives of biochemistry and biophysics | 2015 | PMID: 25978979 |
| Congenital myopathies with secondary neuromuscular transmission defects; a case report and review of the literature. | Rodríguez Cruz PM | Neuromuscular disorders : NMD | 2014 | PMID: 25127990 |
| 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 |
| Frequency and phenotype of patients carrying TPM2 and TPM3 gene mutations in a cohort of 94 patients with congenital myopathy. | Citirak G | Neuromuscular disorders : NMD | 2014 | PMID: 24507666 |
| Mutations in repeating structural motifs of tropomyosin cause gain of function in skeletal muscle myopathy patients. | Marston S | Human molecular genetics | 2013 | PMID: 23886664 |
| Somatic mosaicism in TPM2-related myopathy with nemaline rods and cap structures. | Tasca G | Acta neuropathologica | 2013 | PMID: 23015096 |
| Cap disease due to mutation of the beta-tropomyosin gene (TPM2). | Clarke NF | Neuromuscular disorders : NMD | 2009 | PMID: 19345583 |
| Cap disease caused by heterozygous deletion of the beta-tropomyosin gene TPM2. | Lehtokari VL | Neuromuscular disorders : NMD | 2007 | PMID: 17434307 |
Text-mined citations for rs199476153 ...
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 Jan 04, 2025
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.