TMPO was first reported in relation to hypertrophic cardiomyopathy (HCM) in 1 proband in a single 2019 publication (Huang et al 2019, PMID 31277123). The paper reported the same missense variant (Arg690Cys) previously associated with dilated hypertrophic cardiomyopathy (Taylor et al 2005, PMID 16247757), but was later disputed based on high frequency in the gnomAD database, which is consistent with a benign variation. The second variant reported (Vadrot et al. 2023 PMID 36672271) is a frameshift mutation (Gly395Glufs*11) found in 1 male proband. The pathogenicity of this variant was supported by limited functional studies in a cell culture model system that showed reduced protein level and expression, with decrease in cell proliferation and mislocalized truncated protein fragments in the cytoplasm, however the mechanism of disease phenotype remains unclear. The mechanism for disease is unknown. This gene-disease relationship is not supported by other experimental studies. 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. The relationship between TMPO and autosomal dominant hypertrophic cardiomyopathy was originally evaluated by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel (GCEP) in August 2018 and found to have a no known disease relationship classification. It was re-evaluated in April 2023 by the Hereditary Cardiovascular Disease GCEP. As a result of this recuration, the classification has changed to limited.
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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