TNNT1 was first reported in relation to autosomal dominant nemaline myopathy in 2017 (Konersman CG, et al., 2017, PMID: 29178646). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. To date three missense variants, at or adjacent to the tropomyosin‐binding site 1 region, have been reported in humans occurring in three proband (PMIDs: 29178646, 34440373, 35510366) and at least 8 additional affected family members (PMIDs: 29178646, 35510366). The mechanism for disease is thought to be gain of function but has not been experimentally determined. This gene-disease relationship is supported by its biochemical function in muscle contraction, interaction with additional nemaline myopathy gene TPM2, and expression in skeletal muscle. 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 recessive nemaline myopathy 5. These have been assessed separately. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism (loss of function versus potential gain of function), inheritance pattern (autosomal recessive versus autosomal dominant), and phenotypic variability (the missense autosomal dominant mutation results in a mild phenotype with considerable clinical heterogeneity, whereas the recessive truncating and internal deletion mutations with loss of function are associated with severe, early‐onset phenotypes). Therefore, we have split curations for the disease entities, autosomal dominant nemaline myopathy and autosomal recessive nemaline myopathy 5.
This gene-disease pair was originally approved by the ClinGen Congenital Myopathies Working Group on 06/22/20 (SOP Version 7). It was reevaluated on 03/19/2025. Two additional cases were identified (PMIDs: 34440373, 35510366) and the classification remained at Limited (SOP Version 11).
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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