Submissions for variant NM_000215.4(JAK3):c.1207C>T (p.Arg403Cys)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003064566	SCV003443222	likely pathogenic	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2023-07-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 403 of the JAK3 protein (p.Arg403Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 26915675, 33040328; Invitae). ClinVar contains an entry for this variant (Variation ID: 2138258). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. This variant disrupts the p.Arg403 amino acid residue in JAK3. Other variant(s) that disrupt this residue have been observed in individuals with JAK3-related conditions (PMID: 26545580), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003064566	SCV004804667	uncertain significance	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2024-03-17	criteria provided, single submitter	research