HAVCR2 was first reported in relation to autosomal recessive HAVCR2- related subcutaneous panniculitis-like T-cell lymphoma (SPTCL) and/or hemophagocytic lymphohistiocytosis (HLH) predisposition in 2018 (Gayden et al., PMID: 30374066). Affected individuals typically present with multiple subcutaneous nodules and systemic B-cell symptoms. SPTCL can follow a fulminant course when associated with hemophagocytic lymphohistiocytosis (HLH), which accompanies ~20% of cases and decreases 5 year survival from 90% to less than 50%. As there is a spectrum of SPTCL and HLH outcomes that are considered under one disease assertion, HAVCR2-related SPTCL and/or HLH predisposition, no lumping and splitting was needed for this curation. Five missense variants that have been reported in 37 probands in 8 publications (PMIDs: 30792187, 37062931, 38077348, 30374066, 36212426, 34398459, 34398505, 32285995) are included in this curation. There was a range of different phenotypic manifestations, from isolated SPTCL, to isolated HLH, with some cases reported with both SPTCL and HLH. This gene-disease association is also supported by expression and functional studies (PMIDs: 30374066, 32285995). These experiments indicate that HAVCR2 variants lead to reduced Tim-3 expression and can cause an increased inflammatory response. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP on the meeting date June 10, 2025 (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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