Hereditary Erythrocytosis

Gene: JAK2

Green List (high evidence)

Pathogenic variants have an activating effect on JAK2.
Additional published evidence since the original review. Papers have demonstrated segregation of germline variants with an erythrocytosis phenotype and increased activity of JAK2 / downstream pathways, which is the known mechanism of action for JAK2 mutations causing erythrocytosis in acquired polycythaemia vera.

Created: 24 Nov 2024, 6:55 p.m. | Last Modified: 24 Nov 2024, 6:55 p.m.

Panel Version: 2.6

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Hereditary erythrocytosis

Publications

• PMID: 38629639
• 37639050

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 10 Dec 2025, 2:38 p.m. | Last Modified: 10 Dec 2025, 2:38 p.m.

Panel Version: 2.15

There is limited evidence to support an association of JAK2 variants with hereditary/congenital erythrocytosis. Typically, variants are somatic/acquired; and to date, only one report has described a patient with germline compound het variants (p.E846D and p.R1063H) in JAK2, who exhibited polyclonal erythrocytosis and megakaryocytic atypia but normal platelet number (PMID:27389715).

Note that this condition is distinct from polycythemia vera (PV), which is most commonly associated with JAK2 gain-of-function somatic variants, particularly p.V617F, but also with reports of some familial clustering due to inheritance of the JAK2 46/1 predisposition haplotype. Unlike PV, hereditary erythrocytosis is not associated with the risk of clonal evolution and should present with isolated erythrocytosis, often present since birth.

Created: 25 Sep 2020, 10:56 a.m. | Last Modified: 25 Sep 2020, 10:56 a.m.

Panel Version: 1.14

Mode of inheritance
Other

Phenotypes
Erythrocytosis, somatic, 133100

Publications

• 27389715

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Green List (high evidence)

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).

Created: 31 Mar 2025, 3:24 p.m. | Last Modified: 31 Mar 2025, 3:27 p.m.

Panel Version: 2.11

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.

Created: 31 Mar 2025, 3:13 p.m. | Last Modified: 31 Mar 2025, 3:13 p.m.

Panel Version: 2.10

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.

Created: 22 Sep 2020, 3:11 p.m. | Last Modified: 22 Sep 2020, 3:11 p.m.

Panel Version: 1.12

GMS Expert review Green
Sources: Expert review, NHS GMS

Created: 18 Aug 2020, 4:26 p.m. | Last Modified: 18 Aug 2020, 4:35 p.m.

Panel Version: 1.8

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Hereditary erythrocytosis

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments