NM_152263.4(TPM3):c.137C>T (p.Ala46Val) AND multiple conditions

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 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:: RCV003802400.1

Allele description

NM_152263.4(TPM3):c.137C>T (p.Ala46Val)

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.137C>T (p.Ala46Val)

HGVS:

NC_000001.11:g.154191292G>A
NG_008621.1:g.5842C>T
NM_001364679.2:c.137C>T
NM_001364680.2:c.137C>T
NM_001364681.2:c.137C>T
NM_001364682.1:c.137C>T
NM_152263.4:c.137C>TMANE SELECT
NP_001351608.1:p.Ala46Val
NP_001351609.1:p.Ala46Val
NP_001351610.1:p.Ala46Val
NP_001351611.1:p.Ala46Val
NP_689476.2:p.Ala46Val
LRG_681t2:c.137C>T
LRG_681:g.5842C>T
LRG_681p2:p.Ala46Val
NC_000001.10:g.154163768G>A
NR_103460.2:n.324C>T

Protein change:

A46V

Molecular consequence:

NM_001364679.2:c.137C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001364680.2:c.137C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001364681.2:c.137C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001364682.1:c.137C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_152263.4:c.137C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_103460.2:n.324C>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004608995	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 12, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004608995

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 12, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV004608995.1

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

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 46 of the TPM3 protein (p.Ala46Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of TPM3-related conditions (Invitae). In at least one individual the variant was observed to be de novo. 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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: Jul 29, 2024

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