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11 Dec 2025	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.
11 Dec 2025	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.
11 Dec 2025	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.
12 Apr 2022	Thrombocythaemia v1.3	MPL	Arina Puzriakova Phenotypes for gene: MPL were changed from Thrombocythemia 2, 601977 to Thrombocythemia 2, OMIM:601977
24 Sep 2020	Thrombocythaemia v0.8	CALR	Eleanor Williams changed review comment from: Associated with Myelofibrosis, somatic MIM#254450 and Thrombocythemia, somatic MIM#187950 in OMIM. PMID: 24325356 - Klampfl et al 2013 - performed WES to identify somatically acquired mutations in six patients who had primary myelofibrosis without mutations in JAK2 or MPL. Two patients had somatic deletions in exon 9 of CALR, and the remaining 4 had a recurrent 5-bp insertion. They then screened 382 patients with polycythemia vera, 311 with essential thrombocythemia, and 203 with primary myelofibrosis for alterations in CALR. 78 patients with essential thrombocythemia (25%) and 72 with primary myelofibrosis (35%) had mutations in CALR. All patients with mutated CALR had nonmutated JAK2 and MPL. PMID: 24325359 - Nangalia et al 2013 - performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers. PMID: 31778606 - Jan and Choi 2020 - review of molecular basis of myeloproliferative neoplasms - only somatic mutations mentioned, no germline.; to: Associated with Myelofibrosis, somatic MIM#254450 and Thrombocythemia, somatic MIM#187950 in OMIM. 2 papers report somatic mutations. No germline mutations reported to date. PMID: 24325356 - Klampfl et al 2013 - performed WES to identify somatically acquired mutations in six patients who had primary myelofibrosis without mutations in JAK2 or MPL. Two patients had somatic deletions in exon 9 of CALR, and the remaining 4 had a recurrent 5-bp insertion. They then screened 382 patients with polycythemia vera, 311 with essential thrombocythemia, and 203 with primary myelofibrosis for alterations in CALR. 78 patients with essential thrombocythemia (25%) and 72 with primary myelofibrosis (35%) had mutations in CALR. All patients with mutated CALR had nonmutated JAK2 and MPL. PMID: 24325359 - Nangalia et al 2013 - performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers. PMID: 31778606 - Jan and Choi 2020 - review of molecular basis of myeloproliferative neoplasms - only somatic mutations mentioned, no germline.
20 Aug 2020	Thrombocythaemia v0.1	MPL	Arina Puzriakova reviewed gene: MPL: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
20 Aug 2020	Thrombocythaemia v0.0	MPL	Arina Puzriakova gene: MPL was added gene: MPL was added to Thrombocythaemia. Sources: Expert Review Green,NHS GMS Mode of inheritance for gene: MPL was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: MPL were set to Thrombocythemia 2, 601977