Submissions for variant NM_000215.4(JAK3):c.1744C>T (p.Arg582Trp)

dbSNP: rs193922361

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV001852597	SCV004102769	likely pathogenic	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2023-11-14	reviewed by expert panel	curation	The NM_000215.4(JAK3):c.1744C>T variant is predicted to cause the Arg582Trp missense substitution, however it has been observed in patient cDNA to cause an in-frame deletion of 213bp (71 amino acids; p.Ser568_Leu638del) due to skipping of exon 13 and 14 (PMID: 9753072). The deleted region contains the NM_000215.4(JAK3):c.1796T>G (p.Val599Gly) variant which has been classified by the SCID VCEP as VUS (PM4_supporting). This variant was identified in at least one T-B+ SCID patient in whom, IL-2-induced JAK3 phosphorylation showed that the JAK3 protein was only marginally activated, and IL-2-induced phosphorylation of STAT5B/A was not detected in BCLs from the patient. This combination is highly specific for T-B+ severe combined immunodeficiency due to JAK3 deficiency (PMID: 9753072; PP4_moderate). This patient (PMID: 9753072) was homozygous for the variant and two additional patients are compound heterozygous with second variants confirmed in trans (but not yet classified by the SCID-VCEP so considered VUS), Leu1017Pro (PMID: 33777394) and c.115dup (PMID: 21184155) for three patients in total with this variant (PM3). The highest population allele frequency in gnomAD v2.1.1 is 0.00001239 (1/80718 alleles in the European non-Finnish population), which is lower than the ClinGen SCID VCEP threshold of <0.000115 (PM2_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive T-B+ SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_supporting, PM3, PM4_supporting, PP4_moderate. (VCEP specifications version 1).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030087	SCV000052742	likely pathogenic	Severe combined immunodeficiency disease	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852597	SCV002176241	pathogenic	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 582 of the JAK3 protein (p.Arg582Trp). 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 missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 9753072, 21184155, 30697212, 33365035). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as substitution of Arg to Trp at codon 577. ClinVar contains an entry for this variant (Variation ID: 36415). 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 expected to disrupt JAK3 protein function. Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (PMID: 9753072). For these reasons, this variant has been classified as Pathogenic.