Submissions for variant NM_000215.4(JAK3):c.394C>A (p.Pro132Thr)

gnomAD frequency: 0.02676  dbSNP: rs3212723

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000550265	SCV004242258	benign	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2024-01-23	reviewed by expert panel	curation	The c.394C>A (NM_000215.4) variant in JAK3 is a missense variant predicted to cause substitution of Proline by Threonine at amino acid 132 (p.Pro132Thr). The filtering allele frequency (the lower threshold of the 95% CI of 6500/74518) of the c.394C>A variant in JAK3 is 0.08599 for African/African American chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1, and therefore meets this criterion (BA1). Furthermore, 321 adult homozygous were described in GnomAD v.2.1.1, meeting BS2_Supporting criteria. In summary, this variant meets the criteria to be classified as Benign for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BA1 and BS2_Supporting (VCEP specifications version 1.0).
GeneDx	RCV000121269	SCV000168891	benign	not specified	2013-01-18	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Laboratory Services, Illumina	RCV000550265	SCV000411124	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.
Invitae	RCV000550265	SCV000638326	benign	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2024-01-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000550265	SCV002803176	benign	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2021-07-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003965016	SCV004789769	benign	JAK3-related disorder	2019-04-01	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	RCV000121269	SCV000085440	not provided	not specified	2013-09-19	no assertion provided	reference population
Database of Curated Mutations (DoCM)	RCV000433061	SCV000504895	likely pathogenic	Lymphoblastic leukemia, acute, with lymphomatous features	2015-07-14	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442628	SCV000510432	likely pathogenic	Acute megakaryoblastic leukemia	2016-05-13	no assertion criteria provided	literature only