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Hereditary Erythrocytosis v2.13 SH2B3 Arina Puzriakova edited their review of gene: SH2B3: Added comment: Tagging for GMS expert review to determine whether this gene should be included and the MOI that should be set on this panel. Erythrocytosis is thought to be caused by somatic variants (for somatic variants MOI is set to Other) and testing criteria for this panel states that secondary causes such as myeloproliferative neoplasm should be excluded. However, Terri McVeigh states that germline variants should be included, although these are typically linked to myeloproliferative neoplasms.

Cases of erythrocytosis due to germline variants are rare, and most studies reporting SH2B3 variants have not determined germline or somatic status (PMID: 20843259; 23812944; 27651169; 34349782). In the literature, there is only one report of idiopathic erythrocytosis, without signs of myeloproliferative neoplasms, associated with a confirmed germline heterozygous SH2B3 variant. The mother was also a carrier but had no signs of erythrocytosis (PMID: 38024597).; Changed publications to: 20843259, 23812944, 27651169, 34349782, 38024597
Hereditary Erythrocytosis v2.11 JAK2 Sarah Leigh changed review comment from: At least four JAK2 variants have been associated with Hereditary erythrocytosis (PMID: 38629639; 37639050; 27389715). Three biallelic JAK2 variants have been reported in in two unrelated cases (one case being compound heterozygous PMID: 27389715, and the other being homozygous (PMID: 37639050), the forth variant occurs as a heterozygote in the proband, her mother and daughter (PMID: 38629639). All of these four variants have a hyperactivating effect on JAK2/STAT5 signaling pathway (PMID: 38629639; 37639050; 27389715).; to: At least four JAK2 variants have been associated with Hereditary erythrocytosis (PMID: 38629639; 37639050; 27389715). Three biallelic JAK2 variants have been reported in two unrelated cases (one case being compound heterozygous PMID: 27389715, and the other being homozygous (PMID: 37639050), the forth variant occurs as a heterozygote in the proband, her mother and daughter (PMID: 38629639). All of these four variants have a hyperactivating effect on JAK2/STAT5 signaling pathway (PMID: 38629639; 37639050; 27389715).
Hereditary Erythrocytosis v2.10 JAK2 Sarah Leigh edited their review of gene: JAK2: Added comment: At least four JAK2 variants have been associated with Hereditary erythrocytosis (PMID: 38629639; 37639050; 27389715). Three biallelic JAK2 variants have been reported in in two unrelated cases (one case being compound heterozygous PMID: 27389715, and the other being homozygous (PMID: 37639050), the forth variant occurs as a heterozygote in the proband, her mother and daughter (PMID: 38629639). All of these four variants have a hyperactivating effect on JAK2/STAT5 signaling pathway (PMID: 38629639; 37639050; 27389715).; Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Changed phenotypes to: Hereditary erythrocytosis; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary Erythrocytosis v2.10 JAK2 Sarah Leigh Added comment: Comment on mode of pathogenicity: Functional studies demonstrate that the missense JAK2 variants reported in PMID: 38629639; 37639050; 27389715 all have a gain of funtion.
Hereditary Erythrocytosis v2.5 PKLR Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'both mono- and biallelic' to 'monoallelic' only. Limited evidence but historic reports linked heterozygous variants in the PKLR gene to elevation of red cell ATP levels, accompanied by elevated red cell pyruvate kinase activity and mild erythrocytosis. Patients were asymptomatic and no recent cases have been published therefore Red rating is appropriate (PMIDs: 9090535; 4160306; 14300761; 7426754).

Biallelic variants cause pyruvate kinase deficiency which results in nonspherocytic hemolytic anemia rather than erythrocytosis.
Hereditary Erythrocytosis v1.41 SLC30A10 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by external reviewer Dmitrijs Rots. There is enough evidence to promote this gene to Green at the next GMS panel update. All affected individuals reported to date (>3) had polycythemia at the time of diagnosis, which can precede the onset of neurologic manifestations and therefore it is worth including SLC30A10 on this panel.
Hereditary Erythrocytosis v1.36 BPGM Arina Puzriakova Added comment: Comment on mode of inheritance: Three patients described in literature with biallelic variants (PMID: 1421379; 15054810; 33216349) and 2 with heterozygous variants (PMID: 25015942; 27651169) in the BPGM gene. Heterozygous variants in some cases may cause milder erythrocytosis due to partial BPGM deficiency.

Of the four individuals (2 homo, 2 het) identified in the paper reviewed by Dmitrijs Rots (PMID: 29790589), three variants were classified VUS and the other had been previously reported and therefore these cases could not be included.

Although the number of monoallelic cases does not reach the threshold for inclusion, the evidence supports an association with erythrocytosis. To reduce risk of potentially missed diagnoses the MOI may be considered for update from 'biallelic' to 'both mono- and biallelic' but this will be flagged for further GMS review.

In any case, BPGM should be promoted to Green at the next GMS panel update with the respective MOI based on the decision of the expert working group.
Hereditary Erythrocytosis v1.35 SLC30A10 Dmitrijs Rots gene: SLC30A10 was added
gene: SLC30A10 was added to Hereditary Erythrocytosis. Sources: Literature
Mode of inheritance for gene: SLC30A10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC30A10 were set to PMID: 22341971; 22341972
Phenotypes for gene: SLC30A10 were set to Erythrocytosis; Polycytemia; Hypermanganesemia; Parkinsonism; Dystonia; Liver disease
Review for gene: SLC30A10 was set to GREEN
Added comment: In 6 individuals from two families and 14 individuals from 8 families reported in in 22341971 and 22341972, respectively - all have erythrocytosis/polycytemia.
Sources: Literature
Hereditary Erythrocytosis v1.26 EPOR Arina Puzriakova Phenotypes for gene: EPOR were changed from Polcythaemia; erythrocytosis; Familial Erythrocytosis to [Erythrocytosis, familial, 1], OMIM:133100
Hereditary Erythrocytosis v1.13 SH2B3 Sarah Leigh Added comment: Comment on list classification: An amber rating has been given to SH2B3, as only somatic variants in this gene have been reported to be associated with Erythrocytosis, somatic 133100.
Hereditary Erythrocytosis v1.12 JAK2 Sarah Leigh Added comment: Comment on list classification: An amber rating has been given to JAK2, as only somatic variants in this gene have been reported to be associated with Erythrocytosis, somatic 133100.
Hereditary Erythrocytosis v1.10 BPGM Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in 3 unrelated cases, although two of the cases are biallelic (PMID 25015942, 15054810), one case appears to monoallelic (PMID 25015942).
Hereditary Erythrocytosis EPOR Olivia Niblock marked EPOR as ready
Hereditary Erythrocytosis EPOR Olivia Niblock classified EPOR as green
Hereditary Erythrocytosis EPOR Olivia Niblock commented on EPOR
Hereditary Erythrocytosis EPOR Daniel Gale reviewed EPOR
Hereditary Erythrocytosis EPOR Ellen McDonagh added EPOR to panel
Hereditary Erythrocytosis EPOR Ellen McDonagh reviewed EPOR