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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 12, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000537032.14

Allele description [Variation Report for NM_152263.4(TPM3):c.503G>A (p.Arg168His)]

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

Gene:

TPM3:tropomyosin 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q21.3

Genomic location:

Preferred name:

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

HGVS:

NC_000001.11:g.154172971C>T
NG_008621.1:g.24163G>A
NM_001043351.2:c.392G>A
NM_001043352.2:c.392G>A
NM_001043353.2:c.392G>A
NM_001278188.2:c.194G>A
NM_001278189.2:c.392G>A
NM_001278190.2:c.392G>A
NM_001278191.2:c.122G>A
NM_001349679.2:c.392G>A
NM_001364679.2:c.503G>A
NM_001364680.2:c.503G>A
NM_001364681.2:c.503G>A
NM_001364682.1:c.503G>A
NM_001364683.1:c.392G>A
NM_152263.4:c.503G>AMANE SELECT
NM_153649.4:c.392G>A
NP_001036816.1:p.Arg131His
NP_001036817.1:p.Arg131His
NP_001036818.1:p.Arg131His
NP_001265117.1:p.Arg65His
NP_001265118.1:p.Arg131His
NP_001265119.1:p.Arg131His
NP_001265120.1:p.Arg41His
NP_001336608.1:p.Arg131His
NP_001351608.1:p.Arg168His
NP_001351609.1:p.Arg168His
NP_001351610.1:p.Arg168His
NP_001351611.1:p.Arg168His
NP_001351612.1:p.Arg131His
NP_689476.2:p.Arg168His
NP_705935.1:p.Arg131His
LRG_681t1:c.392G>A
LRG_681t2:c.503G>A
LRG_681t3:c.392G>A
LRG_681:g.24163G>A
LRG_681p1:p.Arg131His
LRG_681p2:p.Arg168His
LRG_681p3:p.Arg131His
NC_000001.10:g.154145447C>T
NM_152263.2:c.503G>A
NM_152263.3:c.503G>A
NR_103461.2:n.491G>A
P06753:p.Arg168His
p.(Arg168His)

Protein change:

R131H; ARG168HIS

Links:

UniProtKB: P06753#VAR_070069; OMIM: 191030.0005; dbSNP: rs121964852

NCBI 1000 Genomes Browser:

rs121964852

Molecular consequence:

NM_001043351.2:c.392G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001043352.2:c.392G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001043353.2:c.392G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001278188.2:c.194G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001278189.2:c.392G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001278190.2:c.392G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001278191.2:c.122G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349679.2:c.392G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001364679.2:c.503G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001364680.2:c.503G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001364681.2:c.503G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001364682.1:c.503G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001364683.1:c.392G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_152263.4:c.503G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_153649.4:c.392G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_103461.2:n.491G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Congenital myopathy 4B, autosomal recessive
Synonyms:: Nemaline myopathy caused by mutation in the tropomyosin 3 gene; Nemaline myopathy 1, autosomal dominant or recessive
Identifiers:: MONDO: MONDO:0012239; MedGen: C5829889; Orphanet: 171433; Orphanet: 171439; Orphanet: 171881; OMIM: 609284

Name:: Congenital myopathy with fiber type disproportion
Synonyms:: Congenital fiber-type disproportion myopathy; Congenital Fiber-Type Disproportion
Identifiers:: MONDO: MONDO:0009711; MedGen: C0546264; Orphanet: 2020

Recent activity

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Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase family protein [Arabidop...
Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase family protein [Arabidopsis thaliana]
gi|240256429|ref|NP_199891.4|

Protein
Priestia aryabhattai strain NWPZ-6 16S ribosomal RNA gene, partial sequence
Priestia aryabhattai strain NWPZ-6 16S ribosomal RNA gene, partial sequence
gi|1820466557|gb|MT184818.1|

Nucleotide
Curtobacterium sp. strain MAIDO-R16b-9 16S ribosomal RNA gene, partial sequence
Curtobacterium sp. strain MAIDO-R16b-9 16S ribosomal RNA gene, partial sequence
gi|1989819652|gb|MW631980.1|

Nucleotide
Psychrobacillus psychrodurans strain CSBB_294 16S ribosomal RNA gene, partial se...
Psychrobacillus psychrodurans strain CSBB_294 16S ribosomal RNA gene, partial sequence
gi|1908372877|gb|MW033762.1|

Nucleotide
Kocuria sp. strain Can_S17 16S ribosomal RNA gene, partial sequence
Kocuria sp. strain Can_S17 16S ribosomal RNA gene, partial sequence
gi|2269694642|gb|ON965346.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000635068	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 12, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 24095155, 22749829, 22798622, 23886664, 12467750, 17376686, 19553118, 21357678, 24507666, 24692096, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000635068

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 12, 2023)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Combined cap disease and nemaline myopathy in the same patient caused by an autosomal dominant mutation in the TPM3 gene.

Malfatti E, Schaeffer U, Chapon F, Yang Y, Eymard B, Xu R, Laporte J, Romero NB.

Neuromuscul Disord. 2013 Dec;23(12):992-7. doi: 10.1016/j.nmd.2013.07.003. Epub 2013 Oct 2.

PubMed [citation]

PMID:: 24095155

Functional effects of congenital myopathy-related mutations in gamma-tropomyosin gene.

Robaszkiewicz K, Dudek E, Kasprzak AA, Moraczewska J.

Biochim Biophys Acta. 2012 Oct;1822(10):1562-9. doi: 10.1016/j.bbadis.2012.06.009. Epub 2012 Jun 27.

PubMed [citation]

PMID:: 22749829

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000635068.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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