NM_152263.4(TPM3):c.43G>C (p.Asp15His) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 7, 2019
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:: RCV000806717.3

Allele description [Variation Report for NM_152263.4(TPM3):c.43G>C (p.Asp15His)]

NM_152263.4(TPM3):c.43G>C (p.Asp15His)

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.43G>C (p.Asp15His)

HGVS:

NC_000001.11:g.154191976C>G
NG_008621.1:g.5158G>C
NM_001364679.2:c.43G>C
NM_001364680.2:c.43G>C
NM_001364681.2:c.43G>C
NM_001364682.1:c.43G>C
NM_152263.4:c.43G>CMANE SELECT
NP_001351608.1:p.Asp15His
NP_001351609.1:p.Asp15His
NP_001351610.1:p.Asp15His
NP_001351611.1:p.Asp15His
NP_689476.2:p.Asp15His
LRG_681t2:c.43G>C
LRG_681:g.5158G>C
LRG_681p2:p.Asp15His
NC_000001.10:g.154164452C>G
NM_152263.3:c.43G>C
NR_103460.2:n.125G>C
p.(Asp15His)

Protein change:

D15H

Links:

dbSNP: rs1553251644

NCBI 1000 Genomes Browser:

rs1553251644

Molecular consequence:

NM_001364679.2:c.43G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001364680.2:c.43G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001364681.2:c.43G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001364682.1:c.43G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_152263.4:c.43G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_103460.2:n.125G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000946731	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 7, 2019)	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

SCV000946731

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 7, 2019)

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000946731.2

#	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 aspartic acid with histidine at codon 15 of the TPM3 protein (p.Asp15His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with congenital hypotonia and muscle weakness (Invitae). ClinVar contains an entry for this variant (Variation ID: 437430). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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: Sep 29, 2024

ClinVar

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