Submission Details

TPM3 was first reported in relation to autosomal recessive TPM3-related myopathy in 1999 (PMID: 10619715). 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. Several unique loss-of-function null variants (e.g. nonsense, splice-site, frameshift) have been reported in humans, in an autosomal recessive manner. Case-level genetic evidence supporting this gene-disease relationship (11 points) includes published reports of at least six probands observed to have loss of function variants and parents who are asymptomatic heterozygous carriers (PMIDs: 10619715, 12196661, 18382475, 19953533, 37393515). Additionally, these probands display various phenotypes, with the majority showing hypotonia, poor head control, inability to walk, scoliosis, Type 1 muscle fiber atrophy/hypotrophy, delayed motor milestones, muscle weakness, and nemaline bodies. 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). Experimental-level genetic evidence supporting this gene-disease relationship scored 3 points. In summary, there is definitive evidence (14 points) to support the relationship between TPM3 and autosomal recessive 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).