NM_003289.4(TPM2):c.398G>C (p.Arg133Pro) AND Arthrogryposis, distal, type 1A

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 8, 2021
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:: RCV001849916.4

Allele description [Variation Report for NM_003289.4(TPM2):c.398G>C (p.Arg133Pro)]

NM_003289.4(TPM2):c.398G>C (p.Arg133Pro)

Gene:

TPM2:tropomyosin 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9p13.3

Genomic location:

Preferred name:

NM_003289.4(TPM2):c.398G>C (p.Arg133Pro)

HGVS:

NC_000009.12:g.35685528C>G
NG_011620.1:g.9530G>C
NM_001301226.2:c.398G>C
NM_001301227.2:c.398G>C
NM_003289.4:c.398G>CMANE SELECT
NM_213674.1:c.398G>C
NP_001288155.1:p.Arg133Pro
NP_001288156.1:p.Arg133Pro
NP_003280.2:p.Arg133Pro
NP_003280.2:p.Arg133Pro
NP_998839.1:p.Arg133Pro
LRG_680t1:c.398G>C
LRG_680t2:c.398G>C
LRG_680:g.9530G>C
LRG_680p1:p.Arg133Pro
LRG_680p2:p.Arg133Pro
NC_000009.11:g.35685525C>G
NM_003289.3:c.398G>C
P07951:p.Arg133Pro
p.(Arg133Pro)

Protein change:

R133P

Links:

UniProtKB: P07951#VAR_071493; dbSNP: rs199476152

NCBI 1000 Genomes Browser:

rs199476152

Molecular consequence:

NM_001301226.2:c.398G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001301227.2:c.398G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_003289.4:c.398G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_213674.1:c.398G>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV002181305	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 8, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17339586, 23678273, 24692096, 32092148, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002181305

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 8, 2021)

germline

clinical testing

PubMed (5)
[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

Distal arthrogryposis and muscle weakness associated with a beta-tropomyosin mutation.

Tajsharghi H, Kimber E, Holmgren D, Tulinius M, Oldfors A.

Neurology. 2007 Mar 6;68(10):772-5.

PubMed [citation]

PMID:: 17339586

First Korean family with a mutation in TPM2 associated with Sheldon-Hall syndrome.

Ko JM, Choi IH, Baek GH, Kim KW.

J Korean Med Sci. 2013 May;28(5):780-3. doi: 10.3346/jkms.2013.28.5.780. Epub 2013 May 2.

PubMed [citation]

PMID:: 23678273
PMCID:: PMC3653094

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002181305.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 133 of the TPM2 protein (p.Arg133Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This missense change has been observed in individual(s) with autosomal dominant TPM2-related conditions (PMID: 24692096). 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. This variant disrupts the p.Arg133 amino acid residue in TPM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17339586, 23678273, 24692096, 32092148). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 140491).

#	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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