NM_152263.4(TPM3):c.8A>C (p.Glu3Ala) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 28, 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:: RCV003813294.2

Allele description [Variation Report for NM_152263.4(TPM3):c.8A>C (p.Glu3Ala)]

NM_152263.4(TPM3):c.8A>C (p.Glu3Ala)

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.8A>C (p.Glu3Ala)

HGVS:

NC_000001.11:g.154192011T>G
NG_008621.1:g.5123A>C
NM_001364679.2:c.8A>C
NM_001364680.2:c.8A>C
NM_001364681.2:c.8A>C
NM_001364682.1:c.8A>C
NM_152263.4:c.8A>CMANE SELECT
NP_001351608.1:p.Glu3Ala
NP_001351609.1:p.Glu3Ala
NP_001351610.1:p.Glu3Ala
NP_001351611.1:p.Glu3Ala
NP_689476.2:p.Glu3Ala
LRG_681t2:c.8A>C
LRG_681:g.5123A>C
LRG_681p2:p.Glu3Ala
NC_000001.10:g.154164487T>G
NR_103460.2:n.90A>C

Protein change:

E3A

Molecular consequence:

NM_001364679.2:c.8A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001364680.2:c.8A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001364681.2:c.8A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001364682.1:c.8A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_152263.4:c.8A>C - missense variant - [Sequence Ontology: SO:0001583]
NR_103460.2:n.90A>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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regulatory protein E2 [Human papillomavirus type 48]
regulatory protein E2 [Human papillomavirus type 48]
gi|9628546|ref|NP_043419.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004609990	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 28, 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

SCV004609990

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 28, 2023)

germline

clinical testing

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

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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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004609990.1

#	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 glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 3 of the TPM3 protein (p.Glu3Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TPM3-related conditions. 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 with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Sep 29, 2024

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