ClinVar Miner

Submissions for variant NM_000215.3(JAK3):c.2164G>A (p.Val722Ile) (rs3213409)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001357996 SCV000513302 benign not provided 2021-06-23 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24728327, 29921932, 10982185, 19282076, 21228398, 26182690, 27884173, 14615376, 33040328)
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000121262 SCV000604052 likely benign not specified 2017-04-17 criteria provided, single submitter clinical testing
Invitae RCV000558788 SCV000638318 benign Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, NK cell-negative 2020-12-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000558788 SCV001287909 likely benign Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, NK cell-negative 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ITMI RCV000121262 SCV000085433 not provided not specified 2013-09-19 no assertion provided reference population
Database of Curated Mutations (DoCM) RCV000436031 SCV000505697 likely pathogenic Acute megakaryoblastic leukemia 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418338 SCV000505698 likely pathogenic Lymphoblastic leukemia, acute, with lymphomatous features 2015-07-14 no assertion criteria provided literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357996 SCV001553619 likely benign not provided no assertion criteria provided clinical testing The JAK3 p.Val722Ile variant was identified in dbSNP (ID: rs3213409), Cosmic (FATHMM predicted neutral; score=0.23), LOVD 3.0 and ClinVar (classified as likely benign by GeneDx and ARUP Laboratories and as benign by Invitae for severe combined immunodeficiency). The variant was also identified in control databases in 2370 of 282750 chromosomes (21 homozygous) at a frequency of 0.008382 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 263 of 10368 chromosomes (freq: 0.02537), European (non-Finnish) in 1573 of 129108 chromosomes (freq: 0.01218), Other in 68 of 7226 chromosomes (freq: 0.00941), Latino in 179 of 35434 chromosomes (freq: 0.005052), South Asian in 143 of 30616 chromosomes (freq: 0.004671), European (Finnish) in 90 of 25118 chromosomes (freq: 0.003583), African in 53 of 24934 chromosomes (freq: 0.002126) and East Asian in 1 of 19946 chromosomes (freq: 0.00005). The V722I variant was identified in the compound heterozygous state in 1/10 patients with severe combined immunodeficiency (SCID) (Roberts_2004_PMID:14615376). Another study identified the variant in the heterozygous state in 1/14 patients with SCID (Schumacher_2000_PMID:10982185). The V722I variant has also been identified somatically in mutliple cancers, including acute myelogenous leukemia, natural killer T-cell lymphoma, acute lymphoblastic leukemia and lung tumors and has been suggested to be an acitivating mutation (Van Allen_2015_PMID:26014096; MacConaill_2014_PMID:25157968; Bergmann_2014_PMID:24446122; Riera_2011_PMID:21599579; Yin_2015_PMID:25146434). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Val722 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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