NM_003289.4(TPM2):c.412GAG[1] (p.Glu139del) AND Arthrogryposis, distal, type 1A

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 4, 2020
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:: RCV000532873.12

Allele description [Variation Report for NM_003289.4(TPM2):c.412GAG[1] (p.Glu139del)]

NM_003289.4(TPM2):c.412GAG[1] (p.Glu139del)

Gene:

TPM2:tropomyosin 2 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

9p13.3

Genomic location:

Preferred name:

NM_003289.4(TPM2):c.412GAG[1] (p.Glu139del)

HGVS:

NC_000009.12:g.35685509CTC[1]
NG_011620.1:g.9544GAG[1]
NM_001301226.2:c.412GAG[1]
NM_001301227.2:c.412GAG[1]
NM_003289.4:c.412GAG[1]MANE SELECT
NM_213674.1:c.412GAG[1]
NP_001288155.1:p.Glu139del
NP_001288156.1:p.Glu139del
NP_003280.2:p.Glu139del
NP_998839.1:p.Glu139del
LRG_680t1:c.412GAG[1]
LRG_680:g.9544GAG[1]
LRG_680p1:p.Glu139del
NC_000009.11:g.35685506CTC[1]
NC_000009.11:g.35685506_35685508del
NM_003289.3:c.415_417delGAG
NM_003289.4:c.415_417delMANE SELECT
p.(Glu139del)

Protein change:

E139del

Links:

OMIM: 190990.0006; dbSNP: rs199476153

NCBI 1000 Genomes Browser:

rs199476153

Molecular consequence:

NM_001301226.2:c.412GAG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001301227.2:c.412GAG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_003289.4:c.412GAG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_213674.1:c.412GAG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]

Condition(s)

Name:: Arthrogryposis, distal, type 1A
Synonyms:: ARTHROGRYPOSIS MULTIPLEX CONGENITA, DISTAL, TYPE I
Identifiers:: MONDO: MONDO:0007157; MedGen: C0220662; Orphanet: 1146; OMIM: 108120

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000630170	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 4, 2020)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 23886664, 25978979, 17434307, 23015096, 24692096, 25127990, 19345583, 24507666, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000630170

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 4, 2020)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

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

Mutations in repeating structural motifs of tropomyosin cause gain of function in skeletal muscle myopathy patients.

Marston S, Memo M, Messer A, Papadaki M, Nowak K, McNamara E, Ong R, El-Mezgueldi M, Li X, Lehman W.

Hum Mol Genet. 2013 Dec 15;22(24):4978-87. doi: 10.1093/hmg/ddt345. Epub 2013 Jul 25.

PubMed [citation]

PMID:: 23886664
PMCID:: PMC3836477

Aberrant movement of β-tropomyosin associated with congenital myopathy causes defective response of myosin heads and actin during the ATPase cycle.

Borovikov YS, Avrova SV, Rysev NA, Sirenko VV, Simonyan AO, Chernev AA, Karpicheva OE, Piers A, Redwood CS.

Arch Biochem Biophys. 2015 Jul;577-578:11-23. doi: 10.1016/j.abb.2015.05.002. Epub 2015 May 13.

PubMed [citation]

PMID:: 25978979

See all PubMed Citations (9)

Details of each submission

From Invitae, SCV000630170.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this in-frame deletion causes increased calcium sensitivity and inhibits myosin binding (PMID: 23886664, 25978979). This variant has been reported in multiple unrelated individuals affected with autosomal dominant cap myopathy and nemaline myopathy (PMID: 17434307, 23015096, 24692096, 25127990), including several affected individuals where it arose de novo (PMID: 19345583, 24507666). ClinVar contains an entry for this variant (Variation ID: 12465). This variant is not present in population databases (ExAC no frequency). This variant, c.415_417del, results in the deletion of 1 amino acid of the TPM2 protein (p.Glu139del), but otherwise preserves the integrity of the reading frame.

#	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: Apr 15, 2024

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