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

dbSNP: rs137853305

Total submissions: 9

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 (https://www.ncbi.nlm.nih.gov/clinvar/variation/12463/). 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