Total submissions: 30
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Mayo Clinic Laboratories, |
RCV001092995 | SCV007134199 | pathogenic | not provided | 2024-10-29 | criteria provided, single submitter | clinical testing | |
| Institute of Human Genetics, |
RCV000015771 | SCV007113990 | pathogenic | Acute myeloid leukemia | 2025-11-11 | criteria provided, single submitter | clinical testing | Criteria applied: PS4,PS3_MOD,PM1,PP4_MOD |
| Genetic Services Laboratory, |
RCV001092995 | SCV006325264 | likely pathogenic | not provided | 2023-12-06 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the JAK2 gene demonstrated a sequence change, c.1849G>T, in exon 14 that results in an amino acid change, p.Val617Phe. The p.Val617Phe change affects a highly conserved amino acid residue located in a domain of the JAK2 protein that is known to be functional. The p.Val617Phe substitution appears to be deleterious/possibly damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been described in the literature in other individuals with JAK2-related disorders in both the germline and somatic state (PMID: 26556299, 31721094, 23535062). In addition, a different pathogenic sequence change affecting the same amino acid residue (p.Val167Ile) has been described in several individuals with JAK2-related hereditary thrombocytosis (PMID: 22397670, 23535062). This sequence change has been described in the gnomAD database with a frequency of 0.075% in the Ashkenazi Jewish subpopulation (dbSNP rs77375493). Collectively, this evidence indicates that this sequence change is likely pathogenic; however, functional studies have not been performed to prove this conclusively. |
| Laboratory of Genetics, |
RCV001092995 | SCV006106468 | pathogenic | not provided | 2025-02-16 | criteria provided, single submitter | clinical testing | |
| 3billion | RCV000015769 | SCV005905726 | likely pathogenic | Acquired polycythemia vera | 2024-02-15 | criteria provided, single submitter | clinical testing | The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset and therefore considered benign. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.88 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014662). A different missense change at the same codon (p.Val617Ile) has been reported to be associated with JAK2 related disorder (ClinVar ID: VCV000029763 /PMID: 22397670). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. |
| Juno Genomics, |
RCV000763621 | SCV005415821 | pathogenic | Primary familial polycythemia due to EPO receptor mutation; Acquired polycythemia vera; Budd-Chiari syndrome; Primary myelofibrosis; Acute myeloid leukemia; Thrombocythemia 3 | criteria provided, single submitter | clinical testing | Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Assumed de novo, but without confirmation of paternity and maternity. | |
| Centre for Clinical Genetics and Genomic Diagnostics, |
RCV001092995 | SCV005328481 | pathogenic | not provided | 2024-02-26 | criteria provided, single submitter | clinical testing | |
| Genomic Medicine Center of Excellence, |
RCV000015769 | SCV004806756 | likely pathogenic | Acquired polycythemia vera | 2024-09-02 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV000015770 | SCV003835086 | pathogenic | Primary myelofibrosis | 2021-08-30 | criteria provided, single submitter | clinical testing | |
| Revvity Omics, |
RCV000022627 | SCV003831788 | likely pathogenic | Thrombocythemia 3 | 2022-10-03 | criteria provided, single submitter | clinical testing | |
| Institute of Human Genetics, |
RCV000015770 | SCV002765070 | pathogenic | Primary myelofibrosis | 2022-11-24 | criteria provided, single submitter | clinical testing | _x000D_ Criteria applied: PS3, PS4, PM1, PM5, PP4 |
| Provincial Medical Genetics Program of British Columbia, |
RCV000015769 | SCV002320869 | pathogenic | Acquired polycythemia vera | 2022-01-01 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001092995 | SCV002307245 | likely pathogenic | not provided | 2026-01-22 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 617 of the JAK2 protein (p.Val617Phe). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant is a well-known somatic change that has been reported as a recurrent variant in many individuals affected with myeloproliferative disorders (PMID: 15920007, 15781101, 15858187, 15793561, 16603627). ClinVar contains an entry for this variant (Variation ID: 14662). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt JAK2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects JAK2 function (PMID: 15793561, 23535062). A different missense substitution at this codon (p.Val617Ile) has been reported to segregate with autosomal dominant hereditary thrombocytosis as a germline change in a single family (PMID: 22397670). Functional studies show that this variant results in constitutive kinase activation and cytokine hyper-responsiveness (PMID: 23535062, 22397670). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Gene |
RCV001092995 | SCV001825403 | pathogenic | not provided | 2025-10-27 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23425079, 25698270, 21120162, 21689158, 27777768, 28205126, 24381227, 16755940, 16293597, 29349042, 31721094, 28596259, 29641446, 23300178, 16156870, 16871278, 20182460, 24068492, 15781101, 19287384, 25157968, 24986690, 16081687, 16709929, 18394554, 24404189, 20339092, 22571758, 20631743, 23115274, 22818858, 22041374, 22829971, 22422826, 21160067, 19549988, 16341032, 26228487, 23537216, 23248577, 23057517, 19195039, 17596137, 17440677, 17194663, 16990759, 16904848, 16954506, 16926301, 15920007, 15858187, 15860661, 26556299, 19293426, 16762626, 15793561, 30944118, 33144682, 32581362, 31447099, 19327411, 27389715, 35861108, 37885353, 35150601) |
| Ce |
RCV001092995 | SCV001249759 | pathogenic | not provided | 2026-02-01 | criteria provided, single submitter | clinical testing | JAK2: PS4, PM1, PP4:Moderate, PS3:Moderate |
| Fulgent Genetics, |
RCV000763621 | SCV000894475 | pathogenic | Primary familial polycythemia due to EPO receptor mutation; Acquired polycythemia vera; Budd-Chiari syndrome; Primary myelofibrosis; Acute myeloid leukemia; Thrombocythemia 3 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Human Genome Sequencing Center Clinical Lab, |
RCV000015769 | SCV000839961 | pathogenic | Acquired polycythemia vera | 2018-02-08 | criteria provided, single submitter | clinical testing | The c.1849G>T (p.V617F) variant in the JAK2 gene is commonly reported as a somatic change in myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia, primary myelofibrosis [PMID: 15781101, 15858187, 15837627, 19074595]. Recently, this variant has also been described as one of the most common drivers of age-related clonal hematopoiesis [PMID: 27563148]. The c.1849G>T (p.V617F) variant in the JAK2 gene is classified as a pathogenic somatic variant. |
| Prevention |
RCV004751211 | SCV005351640 | pathogenic | JAK2-related disorder | 2024-04-30 | no assertion criteria provided | clinical testing | The JAK2 c.1849G>T variant is predicted to result in the amino acid substitution p.Val617Phe. This variant has been reported to be present in almost all patients with polycythemia vera and more than half of those with essential thrombocytosis and primary myelofibrosis (Vassiliou 2016. PubMed ID: 27563148). Somatic c.1849G>T variants have been reported in myeloproliferative neoplasms (Ortmann et al. 2015. PubMed ID: 25671252; Rumi et al. 2014. PubMed ID: 24986690). This variant is reported in 0.058% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. |
| Molecular Diagnostics Laboratory, |
RCV000015769 | SCV004175181 | pathogenic | Acquired polycythemia vera | no assertion criteria provided | provider interpretation | ||
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV001092995 | SCV002037447 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Laboratory of Diagnostic Genome Analysis, |
RCV001092995 | SCV002036319 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| NIHR Bioresource Rare Diseases, |
RCV000427081 | SCV001162251 | pathogenic | Myeloproliferative disorder | no assertion criteria provided | research | ||
| NIHR Bioresource Rare Diseases, |
RCV001003804 | SCV001162250 | pathogenic | Polycythemia | no assertion criteria provided | research | ||
| NIHR Bioresource Rare Diseases, |
RCV001003803 | SCV001162249 | likely pathogenic | Primary myelofibrosis; Splenomegaly | no assertion criteria provided | research | ||
| OMIM | RCV000022628 | SCV000043917 | affects | Primary familial polycythemia due to EPO receptor mutation | 2014-08-07 | no assertion criteria provided | literature only | |
| OMIM | RCV000022627 | SCV000043916 | pathogenic | Thrombocythemia 3 | 2014-08-07 | no assertion criteria provided | literature only | |
| OMIM | RCV000015772 | SCV000036038 | risk factor | Budd-Chiari syndrome, susceptibility to, somatic | 2014-08-07 | no assertion criteria provided | literature only | |
| OMIM | RCV000015771 | SCV000036037 | pathogenic | Acute myeloid leukemia | 2014-08-07 | no assertion criteria provided | literature only | |
| OMIM | RCV000015770 | SCV000036036 | pathogenic | Primary myelofibrosis | 2014-08-07 | no assertion criteria provided | literature only | |
| OMIM | RCV000015769 | SCV000036034 | pathogenic | Acquired polycythemia vera | 2014-08-07 | no assertion criteria provided | literature only |