Submissions for variant NM_004972.4(JAK2):c.1691G>T (p.Arg564Leu)

dbSNP: rs368927897

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001356933	SCV003263035	uncertain significance	not provided	2022-05-20	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 376706). This variant has not been reported in the literature in individuals affected with JAK2-related conditions. This variant is present in population databases (rs368927897, gnomAD 0.03%). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 564 of the JAK2 protein (p.Arg564Leu).
PreventionGenetics, part of Exact Sciences	RCV003418107	SCV004113466	uncertain significance	JAK2-related disorder	2023-10-12	criteria provided, single submitter	clinical testing	The JAK2 c.1691G>T variant is predicted to result in the amino acid substitution p.Arg564Leu. This variant has been reported in patients with chronic myeloproliferative neoplasias (Ma et al. 2009. PubMed ID: 19074595). In addition, another variant (c.1691G>A) affecting the same amino acid (p.Arg564Gln) has been reported in familial essential thrombocytosis (Etheridge et al. 2014. PubMed ID: 24381227). This variant is reported in 0.029% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-5072541-G-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Database of Curated Mutations (DoCM)	RCV000418120	SCV000510418	likely pathogenic	Myeloproliferative disorder	2016-05-13	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356933	SCV001552229	uncertain significance	not provided		no assertion criteria provided	clinical testing	The JAK2 p.Arg564Leu variant was identified in the literature in 3 of 20,000 samples from patients with suspected Myeloproliferative Neoplasias (Ma_2009_PMID:19074595). The variant was also identified in dbSNP (ID: rs368927897) and ClinVar (classified as likely pathogenic by Database of Curated Mutations (DoCM) for Myeloproliferative disorder as a somatic mutation). The variant was identified in control databases in 17 of 280934 chromosomes at a frequency of 0.00006051 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 3 of 10314 chromosomes (freq: 0.000291), European (non-Finnish) in 12 of 128456 chromosomes (freq: 0.000093) and South Asian in 2 of 30264 chromosomes (freq: 0.000066), but was not observed in the African, Latino, East Asian, European (Finnish), or Other populations. The p.Arg564 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.