TNNT3 was first reported in relation to autosomal recessive nemaline myopathy in 2018 (Sandaradura SA, et al., 2018, PMID: 29266598). Evidence supporting this gene-disease relationship includes case-level data and segregation data. Two splice variant has been reported in two patients in two publicatsions (PMIDs: 29266598, 33977145). This gene-disease association is supported by its biochemical function in muscle contraction (PMID: 7721095), its interaction with TNNT1 (PMID: 6447509), its expression in skeletal muscle (PMID: 23775847), and a neonatal lethal mouse model (PMID: 23775847). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.
Of note, this gene has also been implicated in autosomal dominant distal arthrogryposis which will be assessed separately. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in molecular mechanism (loss of function for nemaline myopathy versus a functional alteration due to missense variation at Arg63 for autosomal dominant distal arthrogryposis), inheritance pattern (dominant versus recessive), phenotypic variability (presence of nemaline myopathy and absence of facial features associated with autosomal dominant distal arthrogryposis). Therefore, we have split curations for the disease entities of autosomal recessive nemaline myopathy and autosomal dominant distal arthrogryposis.
This gene-disease pair was originally evaluated by the CM GCEP on 02/24/2020. It was reevaluated on 02/21/2025. As a result of this reevaluation new genetic evidence (PMID: 33977145) was identified however the classification remained at Limited. This second case provided additional evidnece for a gene-diseae relationship with a congenital myopathy though the patient did not have nemaline rods.
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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