Submissions for variant NM_000215.4(JAK3):c.1205G>A (p.Arg402His)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003622200	SCV004539069	likely pathogenic	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2023-06-29	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Arg402 amino acid residue in JAK3. Other variant(s) that disrupt this residue have been observed in individuals with JAK3-related conditions (PMID: 27484032, 28917720, 30290665), which suggests that this may be a clinically significant amino acid residue. 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 not expected to disrupt JAK3 protein function. This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 28917720, 30290665). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs767428670, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 402 of the JAK3 protein (p.Arg402His).