Submissions for variant NM_000215.4(JAK3):c.1767C>T (p.Gly589=)

gnomAD frequency: 0.00001  dbSNP: rs193922362

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030088	SCV000052743	likely pathogenic	Severe combined immunodeficiency disease	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
GeneDx	RCV000256129	SCV000321793	pathogenic	not provided	2016-08-23	criteria provided, single submitter	clinical testing	The c.1767 C>T variant has been published previously in association with SCID (Candotti et al., 1997; Cattaneo et al., 2013). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. While this variant leads to a synonymous amino acid change, several in-silico splice prediction models predict that c.1767 C>T creates a cryptic donor site which may supplant the natural donor site of intron 13 and lead to abnormal gene splicing. Additionally, functional studies have shown that the variant causes the loss of 21 nucleotides upstream of the natural splice donor site, leading to impaired function of the JAK3 protein (Candotti et al., 1997). Therefore, we consider this variant to be pathogenic.
Revvity Omics, Revvity	RCV001781323	SCV002016752	likely pathogenic	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2020-11-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001781323	SCV002303806	uncertain significance	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2021-07-14	criteria provided, single submitter	clinical testing	This sequence change affects codon 589 of the JAK3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the JAK3 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 7 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs193922362, ExAC 0.01%). This variant has been observed in individual(s) with severe combined immunodeficiency (PMID: 9354668, 23384681, 32754152). This variant is also known as a C to T transition at nt 1862. ClinVar contains an entry for this variant (Variation ID: 36416). Studies have shown that this variant results in the activation of a cryptic splice site in exon 13 (PMID: 9354668). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.