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NM_152263.4(TPM3):c.452A>C (p.Glu151Ala) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Sep 13, 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:
RCV003780948.2

Allele description [Variation Report for NM_152263.4(TPM3):c.452A>C (p.Glu151Ala)]

NM_152263.4(TPM3):c.452A>C (p.Glu151Ala)

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.452A>C (p.Glu151Ala)
HGVS:
  • NC_000001.11:g.154173127T>G
  • NG_008621.1:g.24007A>C
  • NM_001043351.2:c.341A>C
  • NM_001043352.2:c.341A>C
  • NM_001043353.2:c.341A>C
  • NM_001278188.2:c.143A>C
  • NM_001278189.2:c.341A>C
  • NM_001278190.2:c.341A>C
  • NM_001278191.2:c.71A>C
  • NM_001349679.2:c.341A>C
  • NM_001364679.2:c.452A>C
  • NM_001364680.2:c.452A>C
  • NM_001364681.2:c.452A>C
  • NM_001364682.1:c.452A>C
  • NM_001364683.1:c.341A>C
  • NM_152263.4:c.452A>CMANE SELECT
  • NM_153649.4:c.341A>C
  • NP_001036816.1:p.Glu114Ala
  • NP_001036817.1:p.Glu114Ala
  • NP_001036818.1:p.Glu114Ala
  • NP_001265117.1:p.Glu48Ala
  • NP_001265118.1:p.Glu114Ala
  • NP_001265119.1:p.Glu114Ala
  • NP_001265120.1:p.Glu24Ala
  • NP_001336608.1:p.Glu114Ala
  • NP_001351608.1:p.Glu151Ala
  • NP_001351609.1:p.Glu151Ala
  • NP_001351610.1:p.Glu151Ala
  • NP_001351611.1:p.Glu151Ala
  • NP_001351612.1:p.Glu114Ala
  • NP_689476.2:p.Glu151Ala
  • NP_705935.1:p.Glu114Ala
  • LRG_681t1:c.341A>C
  • LRG_681t2:c.452A>C
  • LRG_681t3:c.341A>C
  • LRG_681:g.24007A>C
  • LRG_681p1:p.Glu114Ala
  • LRG_681p2:p.Glu151Ala
  • LRG_681p3:p.Glu114Ala
  • NC_000001.10:g.154145603T>G
  • NR_103461.2:n.440A>C
Protein change:
E114A
Molecular consequence:
  • NM_001043351.2:c.341A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001043352.2:c.341A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001043353.2:c.341A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001278188.2:c.143A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001278189.2:c.341A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001278190.2:c.341A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001278191.2:c.71A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001349679.2:c.341A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001364679.2:c.452A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001364680.2:c.452A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001364681.2:c.452A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001364682.1:c.452A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001364683.1:c.341A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_152263.4:c.452A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_153649.4:c.341A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_103461.2:n.440A>C - 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
SCV004569169Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Sep 13, 2023) 		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

Mechanisms of disturbance of the contractile function of slow skeletal muscles induced by myopathic mutations in the tropomyosin TPM3 gene.

Matyushenko AM, Nefedova VV, Shchepkin DV, Kopylova GV, Berg VY, Pivovarova AV, Kleymenov SY, Bershitsky SY, Levitsky DI.

FASEB J. 2020 Oct;34(10):13507-13520. doi: 10.1096/fj.202001318R. Epub 2020 Aug 14.

PubMed [citation]
PMID:
32797717

L-Carnitine ameliorates congenital myopathy in a tropomyosin 3 de novo mutation transgenic zebrafish.

Hsu PJ, Wang HD, Tseng YC, Pan SW, Sampurna BP, Jong YJ, Yuh CH.

J Biomed Sci. 2021 Jan 12;28(1):8. doi: 10.1186/s12929-020-00707-1.

PubMed [citation]
PMID:
33435938
PMCID:
PMC7802209
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004569169.1

#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.Glu151 amino acid residue in TPM3. Other variant(s) that disrupt this residue have been observed in individuals with TPM3-related conditions (PMID: 33435938), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects TPM3 function (PMID: 32797717, 33435938). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TPM3 protein function. This missense change has been observed in individual(s) with clinical features of autosomal dominant congenital myopathy (PMID: 24692096; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 151 of the TPM3 protein (p.Glu151Ala).

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

Last Updated: Sep 29, 2024