TPM3 was first reported in relation to autosomal dominant TPM3-related myopathy in 1995 (Laing et al., PMID: 7704029). Cases of TPM3-related myopathy have historically been categorized by histological features in muscle biopsy and include nemaline myopathy, cap myopathy, and myopathy with fiber-type disproportion on a spectrum of severity. In support of the autosomal dominant form of TPM3-related myopathy, case-level genetic evidence includes at least sixteen probands with unique missense variants in TPM3, including eleven de novo cases (PMIDs: 7704029, 18300303, 20554445, 24692096, 26418456, 33768912, 38219297). These probands display various phenotypes, with the majority showing hypotonia, delayed motor milestones, muscle weakness, fiber atrophy, ptosis, contractures, and Type 1 muscle fiber hypotrophy and predominance. Variants in this gene segregated with disease in three families (1.5 points, PMIDs: 7704029, 18300303). Majority of the missense variants cause a dominant negative effect where the inclusion of mutant TPM3 leads to reduced calcium sensitivity with subsequent reduction in contractile ability, resulting in muscular hypotonia and weakness. Some variants, however, lead to increased calcium sensitivity with subsequent increase in contractile ability, resulting in muscle stiffness. (Marttila et al 2014, PMID: 24692096). This gene-disease association is additionally supported by TPM3's biochemical function, unique expression in the skeletal muscle tissue, physical protein interaction with ACTA1 (PMID: 22749829) and altered function of TPM3 mutant proteins dramatically changing myofilament function (PMID: 21357678). Additionally, a study involving a knock-in mouse model of the well-characterized TPM3 variant Met9Arg recapitulates phenotypes of nemaline and other myopathies similar to those of the human disorder (PMID:11157795). Experimental-level genetic evidence supporting this gene-disease relationship scored 6 points. In summary, there is definitive evidence (13.5 points) to support the relationship between TPM3 and autosomal dominant TPM3-related myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Congenital Myopathies Gene Curation Expert Panel on the meeting date April 8, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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