VCV000012450.34 - ClinVar

NM_152263.4(TPM3):c.503G>A (p.Arg168His)

Germline

Classification

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.

(10)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_152263.4(TPM3):c.503G>A (p.Arg168His)

Variation ID: 12450 Accession: VCV000012450.34

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q21.3 1: 154172971 (GRCh38) [ NCBI UCSC ] 1: 154145447 (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	May 3, 2013	Oct 20, 2024	Apr 12, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_152263.4:c.503G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_689476.2:p.Arg168His	missense
NM_001043351.2:c.392G>A	NP_001036816.1:p.Arg131His	missense
NM_001043352.2:c.392G>A	NP_001036817.1:p.Arg131His	missense
NM_001043353.2:c.392G>A	NP_001036818.1:p.Arg131His	missense
NM_001278188.2:c.194G>A	NP_001265117.1:p.Arg65His	missense
NM_001278189.2:c.392G>A	NP_001265118.1:p.Arg131His	missense
NM_001278190.2:c.392G>A	NP_001265119.1:p.Arg131His	missense
NM_001278191.2:c.122G>A	NP_001265120.1:p.Arg41His	missense
NM_001349679.2:c.392G>A	NP_001336608.1:p.Arg131His	missense
NM_001364679.2:c.503G>A	NP_001351608.1:p.Arg168His	missense
NM_001364680.2:c.503G>A	NP_001351609.1:p.Arg168His	missense
NM_001364681.2:c.503G>A	NP_001351610.1:p.Arg168His	missense
NM_001364682.1:c.503G>A	NP_001351611.1:p.Arg168His	missense
NM_001364683.1:c.392G>A	NP_001351612.1:p.Arg131His	missense
NM_153649.4:c.392G>A	NP_705935.1:p.Arg131His	missense
NR_103461.2:n.491G>A		non-coding transcript variant
NC_000001.11:g.154172971C>T
NC_000001.10:g.154145447C>T
NG_008621.1:g.24163G>A
LRG_681:g.24163G>A
LRG_681t1:c.392G>A	LRG_681p1:p.Arg131His
LRG_681t2:c.503G>A	LRG_681p2:p.Arg168His
LRG_681t3:c.392G>A	LRG_681p3:p.Arg131His
	P06753:p.Arg168His

... more HGVS ... less HGVS

Protein change

R168H, R131H, R65H, R41H

Other names

Canonical SPDI

NC_000001.11:154172970:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

ClinGen: CA144541 UniProtKB: P06753#VAR_070069 OMIM: 191030.0005 dbSNP: rs121964852 VarSome

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
Gene	OMIM	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.
TPM3		-	-	GRCh38 GRCh37	368	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.
Congenital myopathy 4B, autosomal recessive	Pathogenic (2)	criteria provided, single submitter	May 3, 2020	RCV000013263.39
Congenital myopathy 4A, autosomal dominant	Pathogenic (1)	no assertion criteria provided	Oct 1, 2009	RCV000054415.27
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Mar 1, 2023	RCV000128701.29
Congenital myopathy 4B, autosomal recessive Congenital myopathy with fiber type disproportion	Pathogenic (1)	criteria provided, single submitter	Apr 12, 2023	RCV000537032.14
See cases	Pathogenic (1)	criteria provided, single submitter	Apr 26, 2021	RCV001420249.9

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 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 (Nov 01, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001818927.3 First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023	Comment: Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); … (more) Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12467750, 22749829, 23886664, 22798622, 24692096, 17376686, 26307083, 19553118, 18300303, 19953533, 20951040, 32140910, 33333461, 31270709) (less)
Pathogenic (Apr 12, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Congenital myopathy with fiber type disproportion Congenital myopathy 4B, autosomal recessive Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000635068.6 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (10) PubMed: 24095155‚ 24692096‚ 21357678‚ 22749829‚ 22798622‚ 23886664‚ 12467750‚ 17376686‚ 19553118‚ 24507666 Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 168 of the TPM3 protein (p.Arg168His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 168 of the TPM3 protein (p.Arg168His). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg168 amino acid residue in TPM3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24095155, 24692096). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TPM3 function (PMID: 21357678, 22749829, 22798622, 23886664). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TPM3 protein function. ClinVar contains an entry for this variant (Variation ID: 12450). This variant is also known as p.Arg167His. This missense change has been observed in individual(s) with autosomal dominant nemaline myopathy, cap myopathy, congenital myopathy, and congenital fiber type disproportion (PMID: 12467750, 17376686, 19553118, 21357678, 24507666, 24692096). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. (less)
Pathogenic (Aug 29, 2018)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV001146217.1 First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020	Publications: PubMed (14) PubMed: 17376686‚ 19553118‚ 22798622‚ 23886664‚ 24692096‚ 26307083‚ 22749829‚ 21357678‚ 24507666‚ 12467750‚ 24095155‚ 19953533‚ 18300303‚ 20951040 Comment: Not found in the total gnomAD dataset, and the data is high quality (0/277230 chr). Found in at least one symptomatic patient. Conflicting predictions of … (more) Not found in the total gnomAD dataset, and the data is high quality (0/277230 chr). Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Two other pathogenic or likely pathogenic variants affect the same amino acid. Damaging to protein function(s) relevant to disease mechanism. Moderate co-segregation with disease, and data include both affected and unaffected members from multiple families. 3 de novo cases without parental identity confirmed. 1 de novo case with parental identity confirmed. (less)
Pathogenic (May 03, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myopathy 4B, autosomal recessive Affected status: yes Allele origin: unknown	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV001251922.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Pathogenic (Apr 26, 2021)	criteria provided, single submitter (Parc Tauli Hospital Assertion Criteria 2021) Method: clinical testing	See cases (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli Accession: SCV001622669.1 First in ClinVar: May 20, 2021 Last updated: May 20, 2021	Comment: PP5_very strong;PS3_strong;PM2_supporting;PM5_moderate;PP2_supporting;PP3_supporting Clinical Features: Myopathy (present) , Hypotonia (present) Zygosity: Single Heterozygote Sex: female
Pathogenic (Jul 22, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV002520039.1 First in ClinVar: May 27, 2022 Last updated: May 27, 2022	Publications: PubMed (6) PubMed: 17376686‚ 19553118‚ 22749829‚ 22798622‚ 23886664‚ 24692096 Comment: PP1, PP3, PM2, PM6, PS3, PS4_moderate
Pathogenic (Mar 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV003916500.13 First in ClinVar: Apr 23, 2023 Last updated: Oct 20, 2024	Comment: TPM3: PM1, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting Number of individuals with the variant: 1
Pathogenic (Oct 01, 2009)	no assertion criteria provided Method: literature only	CONGENITAL MYOPATHY 4A, AUTOSOMAL DOMINANT Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033510.5 First in ClinVar: Apr 04, 2013 Last updated: Jul 23, 2024	Publications: PubMed (4) PubMed: 17376686‚ 18300303‚ 19553118‚ 1221488 Comment on evidence: In 4 affected members of a French family with autosomal dominant congenital myopathy-4A (CMYO4A; 255310), Penisson-Besnier et al. (2007) identified a heterozygous c.503G-A transition in … (more) In 4 affected members of a French family with autosomal dominant congenital myopathy-4A (CMYO4A; 255310), Penisson-Besnier et al. (2007) identified a heterozygous c.503G-A transition in exon 5 of the TPM3 gene, resulting in an ARG167HIS substitution. Although most patients had symptoms in childhood, all remained ambulatory as adults. Clarke et al. (2008) noted that based on numbering from the first met codon this mutation is designated ARG168HIS (R168H). In a father and daughter with congenital myopathy, Clarke et al. (2008) identified the R168H mutation in the TPM3 gene. Both patients had onset of hypotonia in infancy and were able to run in late adolescence. At age 60, the father could walk, had impaired nocturnal ventilation, showed distal more than proximal weakness, and had scoliosis with lumbar lordosis. Skeletal muscle biopsy was consistent with nemaline myopathy. At age 20, the daughter was able to run, had decreased forced vital capacity, mild proximal weakness, and mild scoliosis. Skeletal muscle biopsy showed fiber-type disproportion (CFTD) The findings of both nemaline myopathy and CFTD in patients with the same mutation showed that TPM3 mutations can cause a range of histologic changes, and suggested that there is a close relation between nemaline myopathy and CFTD. De Paula et al. (2009) reported a 42-year-old man with the R168H mutation who showed cap myopathy on skeletal muscle biopsy. He had hypotonia in the first months of life, delayed motor development, and distal weakness of the lower limbs with frequent falls in childhood. At age 7 years, he had flat feet in valgus, long narrow face, high-arched palate, and mild lumbar hyperlordosis. Tendon reflexes were absent. The clinical course was stable until presentation at age 42 with inability to run, difficulty climbing stairs, and predominant distal muscle weakness. Skeletal muscle biopsy at age 7 years showed type 1 fiber hypotrophy. Biopsy at age 42 years showed only type 1 fibers, irregularity of fiber size, occasional central nuclei, and peripheral eosinophilic-basophilic densely stained substances consistent with 'caps.' The caps were present in about 10 to 15% of muscle fibers, were negative for ATPase staining, were present just beneath the sarcolemma, and consisted of abnormally arranged myofibrils. Z-lines were thickened with some rod-like structures. The authors noted that this case had first been reported as a congenital myopathy with selective hypotrophy of type 1 fibers (Serratrice et al., 1975), and that the biopsy results discussed in that report would have been consistent with CFTD. The findings suggested a relationship between nemaline myopathy, CFTD, and cap myopathy, and indicated that cap structures may develop over time. (less)
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: germline	TPM3 homepage - Leiden Muscular Dystrophy pages Accession: SCV000172341.1 First in ClinVar: Jul 23, 2014 Last updated: Jul 23, 2014
not provided (-)	no classification provided Method: literature only	Congenital myopathy 4B, autosomal recessive Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000058561.2 First in ClinVar: May 03, 2013 Last updated: Oct 01, 2022	Publications: PubMed (3) PubMed: 18300303‚ 19953533‚ 20301436 BookShelf: NBK1259 BookShelf: NBK1259

Comment:

Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12467750, 22749829, 23886664, 22798622, 24692096, 17376686, 26307083, 19553118, 18300303, 19953533, 20951040, 32140910, 33333461, 31270709)

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 168 of the TPM3 protein (p.Arg168His). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg168 amino acid residue in TPM3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24095155, 24692096). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TPM3 function (PMID: 21357678, 22749829, 22798622, 23886664). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TPM3 protein function. ClinVar contains an entry for this variant (Variation ID: 12450). This variant is also known as p.Arg167His. This missense change has been observed in individual(s) with autosomal dominant nemaline myopathy, cap myopathy, congenital myopathy, and congenital fiber type disproportion (PMID: 12467750, 17376686, 19553118, 21357678, 24507666, 24692096). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals.

Comment:

Not found in the total gnomAD dataset, and the data is high quality (0/277230 chr). Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Two other pathogenic or likely pathogenic variants affect the same amino acid. Damaging to protein function(s) relevant to disease mechanism. Moderate co-segregation with disease, and data include both affected and unaffected members from multiple families. 3 de novo cases without parental identity confirmed. 1 de novo case with parental identity confirmed.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Muscle weakness in TPM3-myopathy is due to reduced Ca2+-sensitivity and impaired acto-myosin cross-bridge cycling in slow fibres.	Yuen M	Human molecular genetics	2015	PMID: 26307083
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
Combined cap disease and nemaline myopathy in the same patient caused by an autosomal dominant mutation in the TPM3 gene.	Malfatti E	Neuromuscular disorders : NMD	2013	PMID: 24095155
Mutations in repeating structural motifs of tropomyosin cause gain of function in skeletal muscle myopathy patients.	Marston S	Human molecular genetics	2013	PMID: 23886664
Congenital Fiber-Type Disproportion – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.	Adam MP	-	2013	PMID: 20301436
Congenital myopathy-causing tropomyosin mutations induce thin filament dysfunction via distinct physiological mechanisms.	Ochala J	Human molecular genetics	2012	PMID: 22798622
Functional effects of congenital myopathy-related mutations in gamma-tropomyosin gene.	Robaszkiewicz K	Biochimica et biophysica acta	2012	PMID: 22749829
Changes in cross-bridge cycling underlie muscle weakness in patients with tropomyosin 3-based myopathy.	Ottenheijm CA	Human molecular genetics	2011	PMID: 21357678
Congenital fibre type disproportion associated with mutations in the tropomyosin 3 (TPM3) gene mimicking congenital myasthenia.	Munot P	Neuromuscular disorders : NMD	2010	PMID: 20951040
Mutations of tropomyosin 3 (TPM3) are common and associated with type 1 myofiber hypotrophy in congenital fiber type disproportion.	Lawlor MW	Human mutation	2010	PMID: 19953533
A TPM3 mutation causing cap myopathy.	De Paula AM	Neuromuscular disorders : NMD	2009	PMID: 19553118
Mutations in TPM3 are a common cause of congenital fiber type disproportion.	Clarke NF	Annals of neurology	2008	PMID: 18300303
A second pedigree with autosomal dominant nemaline myopathy caused by TPM3 mutation: a clinical and pathological study.	Pénisson-Besnier I	Neuromuscular disorders : NMD	2007	PMID: 17376686
De novo missense mutation in a constitutively expressed exon of the slow alpha-tropomyosin gene TPM3 associated with an atypical, sporadic case of nemaline myopathy.	Durling HJ	Neuromuscular disorders : NMD	2002	PMID: 12467750
[Congenital myopathy with selective hypotrophy of type I fibers].	Serratrice G	Revue neurologique	1975	PMID: 1221488
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Text-mined citations for rs121964852 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_152263.4(TPM3):c.503G>A (p.Arg168His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121964852 ...