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Thrombocythaemia v1.11 SH2B3 Eleanor Williams changed review comment from: PMID: 41325922 Iaquinta et al 2025 - report of 3 individuals with the same germline heterozygous SH2B3 c.232G>A, p.Glu78Lys variant. They screened 330 patients with myeloproliferative neoplasms with a 73 gene panel. Two of the carriers presented with essential thrombocythemia that progressed to secondary myelofibrosis and one presented with primary myelofibrosis that evolved to acute myeloid leukemia (AML). The variant co-occurred with canonical somatic drivers (CALR or MPL) in the first two cases and with MPL plus additional somatic alterations (SRSF2, TET2) in the third. Distant familial relatedness was not explored. The variant is rare in gnomAD v4.1.0 with a frequency of 0.001097. The authors conclude that heterozygosity alone appears insufficient to drive disease, but supports a low-penetrance predisposition role.

PMID: 40481232 Leardini et al 2025 - 10 children from 9 families with SH2B3-associated neonatal myeloproliferative disease, arising from germline biallelic SH2B3 loss-of-function (LoF) mutations in 8 and in 2 patients with monoallelic germline LoF variants with loss-of-heterozygosity in hematopoietic cells. 9 different variants reported. This was a international, multicenter, retrospective study on paediatric patients with germline variants in SH2B3. Two patients were previously reported in PMID: 38152053. Patients ranged in age from 0–4.0 years. The VAF in blood for patient P8.1 who carries a germline monoallelic variant, was close to 100%, suggesting a near-complete replacement of normal hematopoiesis by the mutant clone. Note: additional somatic driver mutations in other genes were not looked for. Some heterozygous unaffected parents reported. ; to: PMID: 41325922 Iaquinta et al 2025 - report of 3 individuals with the same germline heterozygous SH2B3 c.232G>A, p.Glu78Lys variant. They screened 330 patients with myeloproliferative neoplasms with a 73 gene panel. Two of the carriers presented with essential thrombocythemia that progressed to secondary myelofibrosis and one presented with primary myelofibrosis that evolved to acute myeloid leukemia (AML). The variant co-occurred with canonical somatic drivers (CALR or MPL) in the first two cases and with MPL plus additional somatic alterations (SRSF2, TET2) in the third. Distant familial relatedness was not explored. The variant is rare in gnomAD v4.1.0 with a frequency of 0.001097. The authors conclude that heterozygosity alone appears insufficient to drive disease, but supports a low-penetrance predisposition role.

PMID: 40481232 Leardini et al 2025 - 10 children from 9 families with SH2B3-associated neonatal myeloproliferative disease, arising from germline biallelic SH2B3 loss-of-function (LoF) mutations in 8 and in 2 patients with monoallelic germline LoF variants with loss-of-heterozygosity in hematopoietic cells. 9 different variants reported. This was a international, multicenter, retrospective study on paediatric patients with germline variants in SH2B3. Two patients were previously reported in PMID: 38152053. Patients ranged in age from 0–4.0 years. The VAF in blood for patient P8.1 who carries a germline monoallelic variant, was close to 100%, suggesting a near-complete replacement of normal hematopoiesis by the mutant clone. Note: additional somatic driver mutations in other genes were not looked for. Some heterozygous unaffected parents reported. Heterozygous mother of one homozgyous proband is reported to have had Thrombocytosis from adolescence.
Thrombocythaemia v1.11 SH2B3 Eleanor Williams changed review comment from: PMID: 41325922 Iaquinta et al 2025 - report of 3 individuals with the same germline heterozygous SH2B3 c.232G>A, p.Glu78Lys variant. They screened 330 patients with myeloproliferative neoplasms with a 73 gene panel. Two of the carriers presented with essential thrombocythemia that progressed to secondary myelofibrosis and one presented with primary myelofibrosis that evolved to acute myeloid leukemia (AML). The variant co-occurred with canonical somatic drivers (CALR or MPL) in the first two cases and with MPL plus additional somatic alterations (SRSF2, TET2) in the third. Distant familial relatedness was not explored. The variant is rare in gnomAD v4.1.0 with a frequency of 0.001097. The authors conclude that heterozygosity alone appears insufficient to drive disease, but supports a low-penetrance predisposition role.

PMID: 40481232 Leardini et al 2025 - 10 children from 9 families with SH2B3-associated neonatal myeloproliferative disease, arising from germline biallelic SH2B3 loss-of-function (LoF) mutations in 8 and in 2 patients with monoallelic germline LoF variants with loss-of-heterozygosity in hematopoietic cells. 9 different variants reported. This was a international, multicenter, retrospective study on paediatric patients with germline variants in SH2B3. Two patients were previously reported in PMID: 38152053. Patients ranged in age from 0–4.0 years. The VAF in blood for patient P8.1 who carries a germline monoallelic variant, was close to 100%, suggesting a near-complete replacement of normal hematopoiesis by the mutant clone. Note: additional somatic driver mutations in other genes were not looked for.; to: PMID: 41325922 Iaquinta et al 2025 - report of 3 individuals with the same germline heterozygous SH2B3 c.232G>A, p.Glu78Lys variant. They screened 330 patients with myeloproliferative neoplasms with a 73 gene panel. Two of the carriers presented with essential thrombocythemia that progressed to secondary myelofibrosis and one presented with primary myelofibrosis that evolved to acute myeloid leukemia (AML). The variant co-occurred with canonical somatic drivers (CALR or MPL) in the first two cases and with MPL plus additional somatic alterations (SRSF2, TET2) in the third. Distant familial relatedness was not explored. The variant is rare in gnomAD v4.1.0 with a frequency of 0.001097. The authors conclude that heterozygosity alone appears insufficient to drive disease, but supports a low-penetrance predisposition role.

PMID: 40481232 Leardini et al 2025 - 10 children from 9 families with SH2B3-associated neonatal myeloproliferative disease, arising from germline biallelic SH2B3 loss-of-function (LoF) mutations in 8 and in 2 patients with monoallelic germline LoF variants with loss-of-heterozygosity in hematopoietic cells. 9 different variants reported. This was a international, multicenter, retrospective study on paediatric patients with germline variants in SH2B3. Two patients were previously reported in PMID: 38152053. Patients ranged in age from 0–4.0 years. The VAF in blood for patient P8.1 who carries a germline monoallelic variant, was close to 100%, suggesting a near-complete replacement of normal hematopoiesis by the mutant clone. Note: additional somatic driver mutations in other genes were not looked for. Some heterozygous unaffected parents reported.
Thrombocythaemia v1.11 SH2B3 Eleanor Williams Publications for gene: SH2B3 were set to 28484264; 27237057; 23908464; 40481232
Thrombocythaemia v1.10 SH2B3 Eleanor Williams commented on gene: SH2B3: PMID: 41325922 Iaquinta et al 2025 - report of 3 individuals with the same germline heterozygous SH2B3 c.232G>A, p.Glu78Lys variant. They screened 330 patients with myeloproliferative neoplasms with a 73 gene panel. Two of the carriers presented with essential thrombocythemia that progressed to secondary myelofibrosis and one presented with primary myelofibrosis that evolved to acute myeloid leukemia (AML). The variant co-occurred with canonical somatic drivers (CALR or MPL) in the first two cases and with MPL plus additional somatic alterations (SRSF2, TET2) in the third. Distant familial relatedness was not explored. The variant is rare in gnomAD v4.1.0 with a frequency of 0.001097. The authors conclude that heterozygosity alone appears insufficient to drive disease, but supports a low-penetrance predisposition role.

PMID: 40481232 Leardini et al 2025 - 10 children from 9 families with SH2B3-associated neonatal myeloproliferative disease, arising from germline biallelic SH2B3 loss-of-function (LoF) mutations in 8 and in 2 patients with monoallelic germline LoF variants with loss-of-heterozygosity in hematopoietic cells. 9 different variants reported. This was a international, multicenter, retrospective study on paediatric patients with germline variants in SH2B3. Two patients were previously reported in PMID: 38152053. Patients ranged in age from 0–4.0 years. The VAF in blood for patient P8.1 who carries a germline monoallelic variant, was close to 100%, suggesting a near-complete replacement of normal hematopoiesis by the mutant clone. Note: additional somatic driver mutations in other genes were not looked for.
Thrombocythaemia v1.10 SH2B3 Eleanor Williams Added comment: Comment on phenotypes: Phenotype accessed in OMIM on 11th Dec 2025
Thrombocythaemia v1.10 SH2B3 Eleanor Williams Phenotypes for gene: SH2B3 were changed from Thrombocythemia, somatic, 187950 to Thrombocythemia, somatic, OMIM:187950
Thrombocythaemia v1.9 SH2B3 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: SH2B3.
Tag Q2_25_expert_review was removed from gene: SH2B3.
Tag Q2_25_ NHS_review was removed from gene: SH2B3.
Thrombocythaemia v1.9 SH2B3 Eleanor Williams Added comment: Comment on publications: Adding the PubMed ID of 40481232 for Leardini et al 2025
Thrombocythaemia v1.9 SH2B3 Eleanor Williams Publications for gene: SH2B3 were set to 28484264; 27237057; 23908464
Thrombocythaemia v1.8 SH2B3 Eleanor Williams changed review comment from: The rating of this gene has been updated to green and the mode of inheritance updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval. NW : Other was chosen to capture somatic variants, but is it appropriate to look for those on the R406 panel? MOI should probably be biallelic/monoallelic?NW: Other was chosen to capture somatic variants, but is it appropriate to look for those on the R406 panel? MOI should probably be biallelic/monoallelic?; to: The rating of this gene has been updated to green and the mode of inheritance updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Thrombocythaemia v1.8 SH2B3 Eleanor Williams reviewed gene: SH2B3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thrombocythaemia v1.7 SH2B3 Eleanor Williams Source Expert Review Green was added to SH2B3.
Mode of inheritance for gene SH2B3 was changed from Other to BIALLELIC, autosomal or pseudoautosomal
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Thrombocythaemia v1.6 SH2B3 Arina Puzriakova Tag Q2_25_expert_review tag was added to gene: SH2B3.
Thrombocythaemia v1.6 SH2B3 Arina Puzriakova commented on gene: SH2B3: Tagging for GMS expert review to determine whether this gene should be included and the MOI that should be set on this panel. Both germline and somatic variants have been reported - MOI currently set to Other to capture somatic origin.

Terri McVeigh states that this gene should be included on the panel, although thrombocythaemia typically presents alongside myeloproliferative neoplasm. Testing criteria for this panel states that secondary causes such as myeloproliferative neoplasm should be excluded.
Thrombocythaemia v1.6 SH2B3 Arina Puzriakova Tag Q2_25_ MOI was removed from gene: SH2B3.
Thrombocythaemia v1.6 SH2B3 Sarah Leigh Tag Q2_25_ MOI tag was added to gene: SH2B3.
Thrombocythaemia v1.6 SH2B3 Sarah Leigh Added comment: Comment on publications: https://doi.org/10.1182/blood-2024-210339 does not have a PMID number yet
Thrombocythaemia v1.6 SH2B3 Sarah Leigh Publications for gene: SH2B3 were set to
Thrombocythaemia v1.5 SH2B3 Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: SH2B3.
Tag Q2_25_ NHS_review tag was added to gene: SH2B3.
Thrombocythaemia v1.5 SH2B3 Sarah Leigh reviewed gene: SH2B3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28484264, 27237057, 23908464; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Thrombocythaemia v1.5 SH2B3 Terri McVeigh reviewed gene: SH2B3: Rating: GREEN; Mode of pathogenicity: None; Publications: https://doi.org/10.1182/blood-2024-210339; Phenotypes: thrombocytosis, myeloproliferative disease, ALL; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Thrombocythaemia v0.10 SH2B3 Arina Puzriakova Mode of inheritance for gene: SH2B3 was changed from Unknown to Other
Thrombocythaemia v0.8 SH2B3 Catherine Snow changed review comment from: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, of which one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 when investigating patients with myeloproliferative neoplasms the patient did not have the JAK2 (V617F) variant. Influence of CALR had not been discovered at this time
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, 26 members from five families sequenced with at least two members affected by MPN. A proband who had primary myelofibrosis phenotype had the E208Q SH2B3 variant and a CALR variant (p.L367fs*46) were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and the JAK2 (V617F) variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the E208Q SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 27716218 also identified variant E208Q in SH2B3 and concluded it as a germline variant. Two unrelated families each had two family members with MPNs and the E208Q in SH2B3 variant. Only 2/4 with MPNs had thrombocythaemia all had the JAK2 (V617F) variant, the authors concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Amber as although germline variants have been discovered the Thromobcythaemia phenotype has only been observed when accompanied with additional known somatic variants in JAK2/CALR; to: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, of which one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 when investigating patients with myeloproliferative neoplasms the patient did not have the known JAK2 (V617F) somatic variant. The role of CALR had not been discovered at this time
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, 26 members from five families sequenced with at least two members affected by MPN. A proband who had primary myelofibrosis phenotype had the E208Q SH2B3 variant and a CALR variant (p.L367fs*46) were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and the JAK2 (V617F) variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the E208Q SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 27716218 also identified variant E208Q in SH2B3 and concluded it as a germline variant. Two unrelated families each had two family members with MPNs and the E208Q in SH2B3 variant. Only 2/4 with MPNs had thrombocythaemia all had the JAK2 (V617F) variant, the authors concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Amber as although germline variants have been discovered the Thromobcythaemia phenotype has only been observed when accompanied with additional known somatic variants in JAK2/CALR
Thrombocythaemia v0.8 SH2B3 Catherine Snow changed review comment from: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, sequenced 26 members from five families with at least two members affected by MPN. The proband had primary myelofibrosis phenotype a SH2B3 variant and a CALR variant were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and a JAK2V617F variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 again when investigating patients with myeloproliferative neoplasms.
• PMID 27716218 identified a germline variant in SH2B3 in two families affected members had MPNs but not all had thrombocythaemia and concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Red as although germline variants have been discovered there is no conclusive association of a thrombocythaemia phenotype with these variants.; to: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, of which one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 when investigating patients with myeloproliferative neoplasms the patient did not have the JAK2 (V617F) variant. Influence of CALR had not been discovered at this time
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, 26 members from five families sequenced with at least two members affected by MPN. A proband who had primary myelofibrosis phenotype had the E208Q SH2B3 variant and a CALR variant (p.L367fs*46) were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and the JAK2 (V617F) variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the E208Q SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 27716218 also identified variant E208Q in SH2B3 and concluded it as a germline variant. Two unrelated families each had two family members with MPNs and the E208Q in SH2B3 variant. Only 2/4 with MPNs had thrombocythaemia all had the JAK2 (V617F) variant, the authors concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Amber as although germline variants have been discovered the Thromobcythaemia phenotype has only been observed when accompanied with additional known somatic variants in JAK2/CALR
Thrombocythaemia v0.8 SH2B3 Catherine Snow changed review comment from: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, sequenced 26 members from five families with at least two members affected by MPN. The proband had primary myelofibrosis phenotype a SH2B3 variant and a CALR variant were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and a JAK2V617F variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 again when investigating patients with myeloproliferative neoplasms.
• PMID 27716218 identified a germline variant in SH2B3 in two families affected members had MPNs but not all had thrombocythaemia and concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Red as although germline variants have been discovered there is no conclusive association of a thrombocythaemia phenotype and these variants.; to: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, sequenced 26 members from five families with at least two members affected by MPN. The proband had primary myelofibrosis phenotype a SH2B3 variant and a CALR variant were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and a JAK2V617F variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 again when investigating patients with myeloproliferative neoplasms.
• PMID 27716218 identified a germline variant in SH2B3 in two families affected members had MPNs but not all had thrombocythaemia and concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Red as although germline variants have been discovered there is no conclusive association of a thrombocythaemia phenotype with these variants.
Thrombocythaemia v0.8 SH2B3 Catherine Snow changed review comment from: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, one of the seven diagnostic entities of it is essential Thrombocythaemia.
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, sequenced 26 members from five families with at least two members affected by MPN. The proband had primary myelofibrosis phenotype a SH2B3 variant and a CALR variant were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and a JAK2V617F variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 again when investigating patients with myeloproliferative neoplasms.
• PMID 27716218 identified a germline variant in SH2B3 in two families affected members had MPNs but not all had thrombocythaemia and concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Red as although germline variants have been discovered there is no conclusive association of a thrombocythaemia phenotype and these variants.; to: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, sequenced 26 members from five families with at least two members affected by MPN. The proband had primary myelofibrosis phenotype a SH2B3 variant and a CALR variant were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and a JAK2V617F variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 again when investigating patients with myeloproliferative neoplasms.
• PMID 27716218 identified a germline variant in SH2B3 in two families affected members had MPNs but not all had thrombocythaemia and concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Red as although germline variants have been discovered there is no conclusive association of a thrombocythaemia phenotype and these variants.
Thrombocythaemia v0.8 SH2B3 Catherine Snow Deleted their comment
Thrombocythaemia v0.8 SH2B3 Catherine Snow edited their review of gene: SH2B3: Added comment: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, one of the seven diagnostic entities of it is essential Thrombocythaemia.
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, sequenced 26 members from five families with at least two members affected by MPN. The proband had primary myelofibrosis phenotype a SH2B3 variant and a CALR variant were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and a JAK2V617F variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 again when investigating patients with myeloproliferative neoplasms.
• PMID 27716218 identified a germline variant in SH2B3 in two families affected members had MPNs but not all had thrombocythaemia and concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Red as although germline variants have been discovered there is no conclusive association of a thrombocythaemia phenotype and these variants.; Changed publications: 20404132, 27716218, 27237057
Thrombocythaemia v0.8 SH2B3 Catherine Snow reviewed gene: SH2B3: Rating: RED; Mode of pathogenicity: None; Publications: 20404132, 27716218; Phenotypes: ; Mode of inheritance: Other
Thrombocythaemia v0.1 SH2B3 Arina Puzriakova Tag somatic tag was added to gene: SH2B3.
Thrombocythaemia v0.1 SH2B3 Arina Puzriakova reviewed gene: SH2B3: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Thrombocythaemia v0.0 SH2B3 Arina Puzriakova gene: SH2B3 was added
gene: SH2B3 was added to Thrombocythaemia. Sources: NHS GMS,Expert Review Amber
Mode of inheritance for gene: SH2B3 was set to Unknown
Phenotypes for gene: SH2B3 were set to Thrombocythemia, somatic, 187950