ClinVar Miner

Submissions for variant NM_003289.4(TPM2):c.397C>T (p.Arg133Trp)

dbSNP: rs137853305
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000128682 SCV000859087 pathogenic not provided 2018-01-09 criteria provided, single submitter clinical testing
3billion RCV001775067 SCV002012084 pathogenic Arthrogryposis, distal, type 1A 2021-10-02 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 23678273,17339586, PS1_S). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2).In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.788, 3Cnet: 0.871, PP3). Patient's phenotype is considered compatible with Arthrogryposis, distal, (3billion dataset, PP4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Centogene AG - the Rare Disease Company RCV001775067 SCV002059843 pathogenic Arthrogryposis, distal, type 1A 2019-06-06 criteria provided, single submitter clinical testing
Invitae RCV001775067 SCV002235791 pathogenic Arthrogryposis, distal, type 1A 2021-11-05 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg133 amino acid residue in TPM2. Other variant(s) that disrupt this residue have been observed in individuals with TPM2-related conditions (PMID: 24692096), which suggests that this may be a clinically significant amino acid residue. 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: 12463). This missense change has been observed in individuals with arthrogryposis and/or congenital myopathy (PMID: 17339586, 23678273, 24692096, 32092148). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 133 of the TPM2 protein (p.Arg133Trp).
GeneDx RCV000128682 SCV002546623 pathogenic not provided 2022-06-30 criteria provided, single submitter clinical testing Published functional studies suggest a damaging effect during activation as the variant partially inhibits both calcium- and myosin-induced tropomyosin movement over the thin filament (Ochala et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26307083, 22519952, 23401156, 18422639, 24692096, 23678273, 17339586, 17430991, 31526942, 32092148, 30199282, 31535252, 31864708, 32528171, 20457903, 35579956, 33066566, Neissi2022[Case Report])
PreventionGenetics, part of Exact Sciences RCV004532331 SCV004750518 pathogenic TPM2-related disorder 2023-11-28 criteria provided, single submitter clinical testing The TPM2 c.397C>T variant is predicted to result in the amino acid substitution p.Arg133Trp. This variant has been reported in many unrelated individuals to be causative for TPM2-related disorders (Ochala et al. 2007. PubMed ID 17430991; Marttila et al. 2014. PubMed ID: 24692096; Beck et al. 2013. PubMed ID: 23401156; Table S4, Töpf et al. 2020. PubMed ID: 32528171; Vogt et al. 2020. PubMed ID: 32092148). Functional studies suggested that this variant leads to disrupted regulation of muscle contraction (Ochala et al. 2007. PubMed ID: 17430991). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant is interpreted as pathogenic ( This variant is interpreted as pathogenic.
Suma Genomics RCV001775067 SCV004849373 pathogenic Arthrogryposis, distal, type 1A criteria provided, single submitter clinical testing
OMIM RCV000013279 SCV000033526 pathogenic Arthrogryposis, distal, type 2B4 2013-05-01 no assertion criteria provided literature only
TPM2 homepage - Leiden Muscular Dystrophy pages RCV000128682 SCV000172322 not provided not provided no assertion provided not provided

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