Submission Details

In 2016, the SRC was reported, for the first time, a disease of dominant inheritance, that presented with thrombocytopenia, myelofibrosis, bleeding, and bone pathologies in multiple members from a three-generation pedigree (Turro E, et al., 2016, PMID: 26936507). The patients carried the variant c.1579G>A (p. E527K) in the SRC gene, and the variant segregates with the disease phenotypes in the family (PMID: 26936507). The authors demonstrated that E527K was a gain-of-function variant, which resulted in the loss of SRC’s self-inhibitory capacity. Five additional probands have since been identified with the same variant (PMIDs: 31204551, 35349645, 33054137, 36519321, 36507135). Two were de novo occurrences (PMIDs: 31204551 and 33054137) and one was a Spanish family with seven patients confirmed to harbor E527K (PMID: 35349645). There is also experimental evidence to support the pathogenicity of this variant, including expression of SRC in hematopoietic cells (PMID: 2419901). Additionally, this mutation caused a defect in megakaryopoiesis from either patient cells or the normal stem cell transduced with this change (PMIDs: 26936507 and 33054137). And a Zebrafish model expressing this variant recapitulated the patient’s blood and bone phenotypes (PMID: 26936507). 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 gene-disease pair was originally evaluated by the HT GCEP on 02/26/2020. It was reevaluated on 06/22/2022. As a result of this reevaluation, the classification remained at Moderate with the addition of new case-level evidence (PMIDs: 35349645 and 33054137). It was again reevaluated on 06/03/2024. As a result of this reevaluation, the classification remained at Moderate with the addition of new case-level evidence (PMIDs: 36519321 and 36507135).