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The SH2B3 Database is a curated repository of germline SH2B3 variants identified in patients through published literature. Our goal is to provide a comprehensive knowledge base for understanding germline SH2B3 disorders, which have been recently recognized as novel bone marrow failure predispositions.
If you are interested in contributing variants, please contact wlodarskilab@stjude.org
SH2B3 transcript version is NM_005475.2. Curated by Lili Kotmayer, MD, PhD. Last updated: 07/29/2025.
Patient ID | SH2B3 mutation (cDNA) | SH2B3 mutation (Protein) | Type of mutation | Zygosity | Mutation origin | gnomAD (v4.1.0) population frequency | Year of reporting | PMID | Patient also reported in (PMID) | Original patient ID | Disease | Gender (M/F) | Age at first presentation | Peripheral blood at presentation | Bone marrow at presentation | Cytogenetics | Organomegaly | Autoimmunity | Musculoskeletal changes | Neurocognitive symptoms | Other symptoms | Co-occurring somatic mutations | HSCT | Outcome | Notes |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
P001 | c.671insGGCCCCG | p.Asp231GlyfsX38 | Frameshift | Homozygous | Germline | Absent | 2013 | 23908464 | Sibling 1 (proband) | Autoimmunity only | M | 6 years | Anemia, thrombocytopenia, high WBC at birth | Normocellular with 10-15% blasts, no megakaryocytes | NA | Hepatosplenomegaly | Hashimoto thyroiditis, autoimmune hepatitis | Growth retardation, developmental delay | Speech delay | Alive and well | Consanguineous parents, brother of Sibling 2 | ||||
P002 | c.671insGGCCCCG | p.Asp231GlyfsX38 | Frameshift | Homozygous | Germline | Absent | 2013 | 23908464 | Sibling 2 | B-precursor ALL + autoimmunity | F | 18 months | Normal | Hashimoto thyroiditis, autoimmune hepatitis | Growth retardation, developmental delay | CDKN2A deletion | Consanguineous parents, sister of Sibling 1 (proband) | ||||||||
P003 | c.1279insCTGTTGCCGTGTGC | p.Gln427ProfsX40 | Frameshift | Homozygous | Unknown | Absent | 2013 | 23908464 | Cohort Case 1 | B-precursor ALL | NR | NR | NA | From screening of 167 ALL patients | |||||||||||
P004 | c.1670T>G | p.Leu438Arg | Missense | Homozygous | Germline | Absent | 2024 | 38152053 | 40481232 | UPN3426 / P4.1 | JMML-like, transient | M | 8 months | Thrombocytopenia, leukocytosis, monocytosis, later thrombocytosis | Normal | Hepatosplenomegaly | IUGR, absence of one finger in the right hand | Speech delay | Intracranial and intrahepatic calcifications | Alive, spontaneous improvement | Consanguineous parents | ||||
P005 | c.1175G>A | p.Arg392Gln | Missense | Homozygous | Germline | 0.00068% | 2024 | 38152053 | 40481232 | UPN3436 / P5.1 | JMML | F | 4 months | Leukocytosis, anemia, thrombocytopenia at 4 months | Dysmegakaryopoiesis with 4% blasts | NA | IUGR, growth retardation | Speech and walking delay | yes | Alive and well | Consanguineous parents | ||||
P006 | c.1108C>T | p.Gln251X | Nonsense | Heterozygous | Germline | Absent | 2024 | 38152053 | UPN1744 | JMML | F | 2 months | Leukocytosis, thrombocytopenia | NA | Splenomegaly | yes | Alive 14 years post-HCT | ||||||||
P007 | NA | p.Met211fsX57 | Frameshift | Heterozygous | Germline + somatic LOH | Absent | 2024 | 38152053 | UPN3160 | JMML | M | 4 months | Anemia, leukocytosis, peripheral monocytosis, 5% myeloblasts | Myeloid hyperplasia | Copy-neutral LOH 12q21.1-12q24.33 | yes | Alive, in remission 2 years post-HCT | Responded to ruxolitinib | |||||||
P008 | c.441_468del | p.Arg148ProfsX40 | Frameshift | Homozygous | Germline | 0.000067% | 2023 | 37206266 | Patient 1 | Myeloproliferation + autoimmunity | M | 3 months | Thrombocytosis, neutrophilia | Myeloid hyperplasia with megakaryocytic hyperplasia and atypia | NA | Splenomegaly | Alopecia areata, autoimmune hypothyroidism | Alive and well at age 18 years | |||||||
P009 | c.1204G>A | p.Val402Met | Missense | Homozygous | Germline | 0.00074% | 2023 | 37206266 | Patient 2 | Myeloproliferation + autoimmunity + thrombosis | M | Birth | Persistent thrombocytosis | Mildly hypercellular marrow with megakaryocytic hyperplasia and atypia | NA | Splenomegaly | Autoimmune hypothyroidism, Raynaud syndrome, hepatitis, diabetes | Stroke | Consanguineous parents | ||||||
P010 | c.1160G>C | p.Gly387Ala | Missense | Homozygous | Germline | Absent | 2024 | 37981895 | Patient #79.1 | JMML-like disorder | M | 15 days | Monocytosis, thrombocytopenia, leukocytosis, 6% blasts | Absent megakaryocytes | Normal | Hepatosplenomegaly | IUGR, microcephaly, short stature, growth retardation | Cardiomegaly, tracheomalacia | yes | Alive | Consanguineous parents, brother of #79.2 | ||||
P011 | c.1160G>C | p.Gly387Ala | Missense | Homozygous | Germline | Absent | 2024 | 37981895 | Patient #79.2 | JMML-like disorder | M | 36 days | Monocytosis, thrombocytopenia, leukocytosis, 4% blasts | Normal | Splenomegaly | Autoimmune hypothyroidism | Alive, spontaneous resolution | Consanguineous parents, brother of #79.1 | |||||||
P012 | c.1709dup | p.Asp570LysfsX82 | Frameshift | Homozygous | Germline | Absent | 2024 | 37981895 | OPBG_2 | Neonatal MPD → thrombocytosis | M | 30 days | Initial thrombocytopenia, thrombocytosis at 8 years, 11% blasts | Dysplastic megakaryocytes | Normal | Hepatosplenomegaly | Facial dysmorphic features, complex limb reduction defect | Coronary heart disease | Alive, spontaneous resolution | Consanguineous parents, brother of P2.1 / OPBG_1 | |||||
P013 | c.502G>T + c.1244G>A | p.Glu168X + p.Arg415His | Missense | Compound heterozygous | Germline | p.Glu168X: Absent, p.Arg415His: 0.00037% | 2024 | 37981895 | Patient #201.1 | JMML-like disorder | F | 22 days | Thrombocytopenia, leukocytosis, monocytosis, persistent neutropenia | Absent megakaryocytes | Normal | Hepatosplenomegaly | Alive at 9 years | Sister of #201.2 | |||||||
P014 | c.502G>T + c.1244G>A | p.Glu168X + p.Arg415His | Missense | Compound heterozygous | Germline | p.Glu168X: Absent, p.Arg415His: 0.00037% | 2024 | 37981895 | Patient #201.2 | JMML-like disorder | M | 11 days | Erythrocytosis, thrombocytopenia, leukocytosis, monocytosis, persistent neutropenia | Absent megakaryocytes | NA | Hepatosplenomegaly | Liver cirrhosis | Liver transplant | Alive at 5 years | Brother of #201.1 | |||||
P015 | c.685_691dupGGCCCCG | p.Asp231GlyfsX39 | Frameshift | Homozygous | Germline | Absent (same AA change is in gnomAD) | 2024 | 37981895 | Patient #216 | JMML-like disorder | F | 1 day | Thrombocytopenia, leukocytosis, monocytosis | Normal | Hepatosplenomegaly | Alive at 5 years, spontaneous resolution | Consanguineous parents | ||||||||
P016 | c.1038dup | p.Leu347AlafsX38 | Frameshift | Homozygous | Germline | Absent (same AA change is in gnomAD) | 2024 | 37981895 | Patient #244 | JMML-like disorder | F | 22 days | Thrombocytopenia, leukocytosis, monocytosis | Absent megakaryocytes | Normal | Hepatosplenomegaly | IUGR, facial dysmorphic features | Vermis hematoma and hemoperitoneum | Alive at 2 years with persistent hepatosplenomegaly | Consanguineous parents | |||||
P017 | c.1201T>C | p.Tyr401His | Missense | Heterozygous | Germline | 0.0012% | 2024 | 37981895 | Patient #48 | JMML-like disorder | M | 3.8 years | Thrombocytopenia, monocytosis | Absent megakaryocytes | Normal | Hepatosplenomegaly | PTPN11 | yes | Alive at 19 years | ||||||
P018 | c.685_691dup | p.Asp231GlyfsX39 | Frameshift | Heterozygous | Germline | Absent | 2024 | 37981895 | Patient #53 | JMML-like disorder | M | 2.2 years | Thrombocytopenia, leukocytosis, monocytosis | Normal | Hepatosplenomegaly | Xanthogranuloma | PTPN11 | yes | Death at 17 years following veno- occlusive disease |
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P019 | c.1174C>T | p.Arg392Trp | Missense | Homozygous | Germline | 0.00058% | 2025 | 40481232 | P1.1 | Neonatal MPD | F | 0.1 years | Leukocytosis, mild thrombocytopenia, 6% blasts | NA | Splenomegaly | IUGR, growth retardation, dysmorphic features (low-set and posteriorly rotated ears, prominent forehead with high hair line, mild hypertelorism) | Speech and walking delay | yes | Consanguineous parents, sister of P1.2 | ||||||
P020 | c.1174C>T | p.Arg392Trp | Missense | Homozygous | Germline | 0.00058% | 2025 | 40481232 | P1.2 | Neonatal MPD | F | Birth | Leukocytosis, thrombocytopenia, 2% blasts | NA | Splenomegaly | IUGR, growth retardation, dysmorphic features (low-set and posteriorly rotated ears, prominent forehead with high hair line, mild hypertelorism) | Speech and walking delay | yes | Consanguineous parents, sister of P1.1 | ||||||
P021 | c.1709dup | p.Asp570LysfsX82 | Frameshift | Homozygous | Germline | Absent | 2025 | 40481232 | 37981895 | P2.1 / OPBG_1 | Neonatal MPD → thrombocytosis | F | 30 days | Initial thrombocytopenia, thrombocytosis at 8 years, 11% blasts | Absent megakaryocytes, dysplasia | Normal | Hepatosplenomegaly | Multiple sclerosis, diabetes | IUGR, growth retardation, facial dysmorphic features | Speech and walking delay | Coronary heart disease, persistent Botallo duct | SETBP1 | yes, for grade 3 myelofibrosis at age 10 years | Alive, spontaneous resolution | Consanguineous parents, sister of OPBG_2 |
P022 | c.1A>G | p.? | Start loss | Homozygous | Germline | Absent | 2025 | 40481232 | P3.1 | Isolated thrombocytosis | M | 0.3 years | Thrombocytosis | NA | |||||||||||
P023 | c.832A>T | p.Lys278X | Nonsense | Homozygous | Germline | Absent | 2025 | 40481232 | P6.1 | Neonatal MPD → thrombocytosis | M | 0.1 years | Leukocytosis, initial thrombocytopenia, thrombocytosis at 0.2 years | NA | Hepato/splenomegaly | Autoimmune hypothyroidism, localized scleroderma | Microcephaly, IUGR, growth retardation | Mild global developmental delay and cognitive impairment | |||||||
P024 | c.1198G>A + c.1183G>A | p.Glu400Lys + p.Glu395Lys | Missense | Compound heterozygous | Germline | p.Glu400Lys: 0.14%, p.Glu395Lys: 0.035% | 2025 | 40481232 | P7.1 | Isolated thrombocytosis | M | 4.0 years | Thrombocytosis at 4 years | NA | |||||||||||
P025 | c.833del | p.Lys278ArgfsX2 | Frameshift | Heterozygous | Germline + somatic LOH | Absent | 2025 | 40481232 | P8.1 | Neonatal MPD → thrombocytosis | F | 0.2 years | Leukocytosis, thrombocytosis, 4% blasts | NA | Hepato/splenomegaly | Severe cognitive impairment, autism | SH2B3 LOH | ||||||||
P026 | c.1159G>T | p.Gly387X | Nonsense | Heterozygous | Germline + somatic LOH | Absent | 2025 | 40481232 | P9.1 | Neonatal MPD | F | 0.7 years | Leukocytosis, 2% blasts | NA | Hepato/splenomegaly | SH2B3 LOH | Lost to follow up | ||||||||
P027 | c.1198G>A | p.Glu400Lys | Missense | Heterozygous | Germline | 0.14% | 2019 | 31173385 | Patient 1 | MDS/MPN-RS-T | M | Early 60s | Progressive anemia, macrocytosis, and thrombocytosis | MDS/MPN-overlap syndrome with RS | Normal | On aspirin | |||||||||
P028 | c.1004_1005del | p.Thr335ArgfsX4 | Frameshift | Heterozygous | Germline | Absent | 2023 | 38024597 | Patient 1 | Erythrocytosis | M | 31 years | Polycythemia, mild thrombocytopenia | Normal | Smoker, mother is a carrier | ||||||||||
P029 | c.3G>A | p.? | Start loss | Heterozygous | Germline | Absent | 2022 | 35570682 | #03 | Primary myelofibrosis | F | 51 years | NA | JAK V617F, TET2, other JAK2 | Mother of #01 | ||||||||||
P030 | c.3G>A | p.? | Start loss | Heterozygous | Germline | Absent | 2022 | 35570682 | #01 | Essential thrombocytosis | F | 21 years | NA | JAK V617F | Daughter of #03 | ||||||||||
P031 | c.1183G>A | p.Glu395Lys | Missense | Heterozygous | Germline | 0.035% | 2022 | 35281324 | 37-year-old Caucasian woman | CMML without excess blasts | F | 37 years | Initially leukocytosis, thrombocytosis | NA | Multiple sclerosis | ||||||||||
P032 | c.622G>C | p.Glu208Gln | Missense | Heterozygous | Germline | 0.066% | 2016 | 27237057 | F1 | Primary myelofibrosis | F | 54 years | NA | JAK V617F, CALR, ASXL1, TET2, NRAS, KRAS | Mother of F2 | ||||||||||
P033 | c.622G>C | p.Glu208Gln | Missense | Heterozygous | Germline | 0.066% | 2016 | 27237057 | F2 | Essential thrombocytosis | F | 37 years | NA | Daughter of F1 | |||||||||||
P034 | c.622G>C | p.Glu208Gln | Missense | Heterozygous | Germline | 0.066% | 2024 | 39672944 | 49-year-old woman | Primary myelofibrosis | F | 49 years | NA | Splenomegaly | Psoriasis | Major depressive disorder | Uterine fibroma | JAK V617F | yes | Responded to ruxolitinib |
ALL: acute lymphoblastic leukemia, CMML: chronic myelomonocytic leukemia, HSCT: hematopoietic stem cell transplantation, IUGR: intrauterine growth retardation, JMML: juvenile myelomonocytic leukemia, LOH: loss of heterozygosity, MDS: myelodysplastic syndrome, MPD: myeloproliferative disorder, MDS/MPN-RS-T: myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis, NA: not available, MPN: myeloproliferative neoplasm, RS: ring sideroblasts, WBC: white blood cell