ClinVar Miner

Submissions for variant NM_004972.4(JAK2):c.1849G>T (p.Val617Phe)

gnomAD frequency: 0.00036  dbSNP: rs77375493
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Total submissions: 28
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine 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.
Fulgent Genetics, 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
CeGaT Center for Human Genetics Tuebingen RCV001092995 SCV001249759 pathogenic not provided 2024-01-01 criteria provided, single submitter clinical testing JAK2: PM1, PM5, PM6, PS4:Moderate, PP4, PS3:Supporting
GeneDx RCV001092995 SCV001825403 pathogenic not provided 2023-04-27 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: induces rapid tumorigenesis in mice, and leads to constitutive activation of the JAK2 kinase, excess JAK/STAT signaling, and increased cell survival and proliferation (Kralovics et al., 2005; James et al., 2005; Abe et al., 2009; Kapralova et al., 2016); 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)
Labcorp Genetics (formerly Invitae), Labcorp RCV001092995 SCV002307245 likely pathogenic not provided 2024-01-20 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Provincial Medical Genetics Program of British Columbia, University of British Columbia RCV000015769 SCV002320869 pathogenic Acquired polycythemia vera 2022-01-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000015770 SCV002765070 pathogenic Primary myelofibrosis 2022-11-24 criteria provided, single submitter clinical testing _x000D_ Criteria applied: PS3, PS4, PM1, PM5, PP4
Revvity Omics, Revvity RCV000022627 SCV003831788 likely pathogenic Thrombocythemia 3 2022-10-03 criteria provided, single submitter clinical testing
Baylor Genetics RCV000015770 SCV003835086 pathogenic Primary myelofibrosis 2021-08-30 criteria provided, single submitter clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000015769 SCV004806756 likely pathogenic Acquired polycythemia vera 2024-09-02 criteria provided, single submitter clinical testing
OMIM RCV000015769 SCV000036034 pathogenic Acquired polycythemia vera 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 RCV000015771 SCV000036037 pathogenic Acute myeloid leukemia 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 RCV000022627 SCV000043916 pathogenic Thrombocythemia 3 2014-08-07 no assertion criteria provided literature only
OMIM RCV000022628 SCV000043917 affects Primary familial polycythemia due to EPO receptor mutation 2014-08-07 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420273 SCV000504652 not provided Chronic myelogenous leukemia, BCR-ABL1 positive 2016-03-10 no assertion provided literature only
Database of Curated Mutations (DoCM) RCV000427081 SCV000504653 likely pathogenic Myeloproliferative disorder 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000015770 SCV000504655 likely pathogenic Primary myelofibrosis 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000015771 SCV000504656 likely pathogenic Acute myeloid leukemia 2014-10-02 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428162 SCV000504657 not provided Subacute lymphoid leukemia 2016-03-10 no assertion provided literature only
Database of Curated Mutations (DoCM) RCV000015769 SCV000504658 not provided Acquired polycythemia vera 2016-03-10 no assertion provided literature only
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003803 SCV001162249 likely pathogenic Primary myelofibrosis; Splenomegaly no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003804 SCV001162250 pathogenic Polycythemia no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000427081 SCV001162251 pathogenic Myeloproliferative disorder no assertion criteria provided research
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV001092995 SCV002036319 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001092995 SCV002037447 pathogenic not provided no assertion criteria provided clinical testing
Molecular Diagnostics Laboratory, University of Rochester Medical Center RCV000015769 SCV004175181 pathogenic Acquired polycythemia vera no assertion criteria provided provider interpretation

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