Submissions for variant NM_000215.4(JAK3):c.115dup (p.Gln39fs)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003228198	SCV003924285	pathogenic	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2023-05-08	criteria provided, single submitter	research
Neuberg Centre For Genomic Medicine, NCGM	RCV003340669	SCV004048123	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency		criteria provided, single submitter	clinical testing	The frameshift variant c.115dup (p.Gln39ProfsTer13) in JAK3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Gln39ProfsTer13 variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.001282% is reported in gnomAD. This variant causes a frameshift starting with codon Glutamine 39, changes this amino acid to Proline residue, and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Gln39ProfsTer13. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003228198	SCV004298114	pathogenic	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln39Profs*13) in the JAK3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in JAK3 are known to be pathogenic (PMID: 7481768, 11668621). 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 premature translational stop signal has been observed in individual(s) with severe combined immunodeficiency (PMID: 21184155). 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 c.115-116insC. ClinVar contains an entry for this variant (Variation ID: 2501779). For these reasons, this variant has been classified as Pathogenic.