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NM_152263.4(TPM3):c.271C>T (p.Arg91Cys) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Aug 9, 2022
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:
RCV000808390.7

Allele description [Variation Report for NM_152263.4(TPM3):c.271C>T (p.Arg91Cys)]

NM_152263.4(TPM3):c.271C>T (p.Arg91Cys)

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.271C>T (p.Arg91Cys)
HGVS:
  • NC_000001.11:g.154176221G>A
  • NG_008621.1:g.20913C>T
  • NM_001043351.2:c.160C>T
  • NM_001043352.2:c.160C>T
  • NM_001043353.2:c.160C>T
  • NM_001278188.2:c.69-3020C>T
  • NM_001278189.2:c.160C>T
  • NM_001278190.2:c.160C>T
  • NM_001278191.2:c.-111C>T
  • NM_001349679.2:c.160C>T
  • NM_001364679.2:c.271C>T
  • NM_001364680.2:c.271C>T
  • NM_001364681.2:c.271C>T
  • NM_001364682.1:c.271C>T
  • NM_001364683.1:c.160C>T
  • NM_152263.4:c.271C>TMANE SELECT
  • NM_153649.4:c.160C>T
  • NP_001036816.1:p.Arg54Cys
  • NP_001036817.1:p.Arg54Cys
  • NP_001036818.1:p.Arg54Cys
  • NP_001265118.1:p.Arg54Cys
  • NP_001265119.1:p.Arg54Cys
  • NP_001336608.1:p.Arg54Cys
  • NP_001351608.1:p.Arg91Cys
  • NP_001351609.1:p.Arg91Cys
  • NP_001351610.1:p.Arg91Cys
  • NP_001351611.1:p.Arg91Cys
  • NP_001351612.1:p.Arg54Cys
  • NP_689476.2:p.Arg91Cys
  • NP_705935.1:p.Arg54Cys
  • LRG_681t1:c.160C>T
  • LRG_681t2:c.271C>T
  • LRG_681t3:c.160C>T
  • LRG_681:g.20913C>T
  • LRG_681p1:p.Arg54Cys
  • LRG_681p2:p.Arg91Cys
  • LRG_681p3:p.Arg54Cys
  • NC_000001.10:g.154148697G>A
  • NM_152263.3:c.271C>T
  • NR_103461.2:n.259C>T
Protein change:
R54C
Links:
dbSNP: rs1571418855
NCBI 1000 Genomes Browser:
rs1571418855
Molecular consequence:
  • NM_001278191.2:c.-111C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001278188.2:c.69-3020C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001043351.2:c.160C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001043352.2:c.160C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001043353.2:c.160C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001278189.2:c.160C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001278190.2:c.160C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001349679.2:c.160C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001364679.2:c.271C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001364680.2:c.271C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001364681.2:c.271C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001364682.1:c.271C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001364683.1:c.160C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_152263.4:c.271C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_153649.4:c.160C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_103461.2:n.259C>T - 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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000948498Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Aug 9, 2022) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutations of tropomyosin 3 (TPM3) are common and associated with type 1 myofiber hypotrophy in congenital fiber type disproportion.

Lawlor MW, Dechene ET, Roumm E, Geggel AS, Moghadaszadeh B, Beggs AH.

Hum Mutat. 2010 Feb;31(2):176-83. doi: 10.1002/humu.21157.

PubMed [citation]
PMID:
19953533
PMCID:
PMC2815199

Congenital myopathy-related mutations in tropomyosin disrupt regulatory function through altered actin affinity and tropomodulin binding.

Moraczewska J, Robaszkiewicz K, Śliwinska M, Czajkowska M, Ly T, Kostyukova A, Wen H, Zheng W.

FEBS J. 2019 May;286(10):1877-1893. doi: 10.1111/febs.14787. Epub 2019 Mar 5.

PubMed [citation]
PMID:
30768849
PMCID:
PMC7202179
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000948498.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg91 amino acid residue in TPM3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19953533). 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: 30768849). 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 expected to disrupt TPM3 protein function. ClinVar contains an entry for this variant (Variation ID: 652762). This missense change has been observed in individuals with autosomal dominant congenital myopathy (PMID: 24692096; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 91 of the TPM3 protein (p.Arg91Cys).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jan 13, 2025