Submissions for variant NM_000215.4(JAK3):c.2164G>A (p.Val722Ile)

gnomAD frequency: 0.00743  dbSNP: rs3213409

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000558788	SCV004809132	benign	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2024-04-03	reviewed by expert panel	curation	NM_000215.4(JAK3):c.2164G>A is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 722 (p.Val722Ile). The filtering allele frequency (the lower threshold of the 95% CI of 12957/1180016) of the c.2164G>A variant in JAK3 is 0.01082 for European (non-Finnish) chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1, and therefore meets this criterion (BA1). Additionally, 120 adult homozygous occurrences are reported in gnomAD v4 (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BA1 and B2_Supporting (VCEP specifications version 1).
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	RCV000558788	SCV000604052	likely benign	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2023-10-23	criteria provided, single submitter	clinical testing
Invitae	RCV000558788	SCV000638318	benign	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000558788	SCV001287909	likely benign	T-B+ severe combined immunodeficiency due to JAK3 deficiency	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.
Fulgent Genetics, Fulgent Genetics	RCV000558788	SCV002807031	likely benign	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2022-04-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001357996	SCV004033656	benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	JAK3: BP4, BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003915209	SCV004729929	benign	JAK3-related disorder	2024-01-28	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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.
GenomeConnect, ClinGen	RCV001357996	SCV002074686	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing.