Submissions for variant NM_000215.4(JAK3):c.175A>T (p.Lys59Ter)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV002797190	SCV004102766	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.175A>T (p.Lys59Ter) variant in JAK3 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 2/24 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with JAK3-related conditions, and functional studies have not been found. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1 and PM2_supporting. (VCEP specifications version 1).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002797190	SCV003199567	pathogenic	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2022-05-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys59*) 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with JAK3-related conditions. For these reasons, this variant has been classified as Pathogenic.