Mendeliome
Gene: JAK2 Green List (high evidence)Green List (high evidence)
Association with erythrocytosis:
PMID 35764421: Reports 3 individuals from a single family with heterozygous germline JAK2 p.E846D missense variants presenting with adult‑onset erythrocytosis, elevated haemoglobin/haematocrit and no thrombosis.
PMID 38629639: Reports 3 individuals from a single family with a heterozygous germline JAK2 R715T missense gain‑of‑function variant presenting with PV‑like erythrocytosis (elevated Hb, low‑normal EPO, no thrombocytosis/leukocytosis). Detailed clinical data for proband, mother and son are provided, together with in‑vitro luciferase, Ba/F3‑EPOR proliferation, p‑STAT5 and EPO‑independent BFU‑E assays demonstrating increased JAK‑STAT signalling. Ropeg‑IFNα treatment induced remission in proband and mother.Created: 26 May 2026, 2:21 p.m.
PMID 41053421: three individuals with germline c.1691 G > A, p.Arg564Gln (R564Q) gain-of-function variant and thrombocytosis.
PMID 39657124: Reports 12 individuals from 10 families with heterozygous germline JAK2 p.R564Q/L variants presenting with hereditary thrombocythemia (HT) and variable predisposition to myeloproliferative neoplasms (ET, PV) and lymphoid malignancies (CLL, AML, MGUS).
PMID 39323414: Reports 8 individuals from a single family with heterozygous germline JAK2 F556V gain‑of‑function variants presenting with familial thrombocytosis (hereditary thrombocythemia).
Overall, sufficient cases with germline variants for GREEN rating.Created: 26 May 2026, 12:06 p.m.
Thrombocythemia: original family reported with missense variant in PMID 22397670. Variant is present in gnomad in 97 individuals (March 2022). Another individual reported with variant at same residue PMID 35129130.
Somatic variants in this gene are well established as contributing a range of haematological phenotypes, including erythrocytosis, myelofibrosis, polycythaemia rubra vera, AML.Created: 7 Mar 2022, 9:16 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Thrombocythaemia 3, MIM# 614521; Familial polycythemia MONDO:0001115, JAK2-related
Publications
Phenotypes for gene: JAK2 were changed from Thrombocythaemia 3, MIM# 614521 to Thrombocythaemia 3, MIM# 614521; Familial polycythemia MONDO:0001115, JAK2-related
Publications for gene: JAK2 were set to 22397670; 35129130; 41053421; 39657124; 39323414
Publications for gene: JAK2 were set to 22397670; 35129130
Gene: jak2 has been classified as Green List (High Evidence).
Gene: jak2 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: JAK2 were changed from to Thrombocythaemia 3, MIM# 614521
Publications for gene: JAK2 were set to
Mode of inheritance for gene: JAK2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Gene: jak2 has been classified as Amber List (Moderate Evidence).
Tag somatic tag was added to gene: JAK2.
gene: JAK2 was added gene: JAK2 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: JAK2 was set to Unknown
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.