TET2 is involved in clonal hematopoiesis of indeterminate potential and has been curated independently for a role of somatic variants in cancer. Since the mechanism in pulmonary arterial hypertension (PAH) is through autosomal dominantly acting germline variants, the curations were split instead of lumped. TET2 was first reported in relation to autosomal dominant pulmonary arterial hypertension (PAH) in 2020 (Potus et al., PMID: 32192357). Out of a cohort of 2572 cases from the PAH biobank, 6 rare predicted deleterious likely germline variants including missense, nonsense, and frameshift variants were identified in 6 unrelated individuals. The relationship between TET2 and PAH is also supported by experimental evidence including tissue expression in controls and patients, biochemical function as a negative regulator of a proinflammatory response, and Tet2 knockout mice exhibiting a PH phenotype. In summary, there is moderate 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. This classification was approved by the ClinGen PH Gene Curation Expert Panel on 4/6/2022.
The gene-disease relationship was re-evaluated on 12 February 2025 by the ClinGen PH Gene Curation Expert Panel (SOP v10). This record underwent administrative updates to correct typographical errors. New genetic data (PMIDs: 38116660, 39849426) and expression data (PMIDs: 35581740, 37146099) were reviewed but did not add any new evidence for a gene-disease relationship with H/IPAH. As a result of this re-evaluation, the classification did not change.
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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