Submissions for variant NM_000215.4(JAK3):c.2680+3G>C

gnomAD frequency: 0.00003  dbSNP: rs749481781

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000346279	SCV000411102	uncertain significance	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2017-04-28	criteria provided, single submitter	clinical testing	The JAK3 c.2680+3G>C variant has been reported in three studies, all of which describe the same two siblings with severe combined immune deficiency who carry the variant in a compound heterozygous state (Mella et al. 2001; Notarangelo et al. 2001; Frucht et al. 2001). One sibling presented with a very severe phenotype and the other with a mild, nearly normal phenotype, but both siblings were found to carry the c.2680+3G>C variant along with an initiator codon variant. The c.2680+3G>C variant was also found in a heterozygous state in their unaffected mother (Frucht et al. 2001). The variant was absent from 100 healthy control chromosomes and is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium, but this is based on one allele, so the variant is presumed to be rare. Analysis of cDNA from the sibling with the mild phenotype showed that the c.2680+3G>C variant results in both normally spliced exon 18 and a product containing an intronic sequence that leads to a premature termination of the protein (Frucht et al. 2001). Based on the evidence, the c.2680+3G>C variant is classified as a variant of unknown significance but suspicious for pathogenicity for severe combined immune deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000346279	SCV002971615	pathogenic	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change falls in intron 19 of the JAK3 gene. It does not directly change the encoded amino acid sequence of the JAK3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs749481781, gnomAD 0.003%). This variant has been observed in individual(s) with severe combined immunodeficiency and/or partial JAK3 deficiency (PMID: 11668621, 11781709). 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 intron 18 G2775(+3)C or IVS18+3G>C. ClinVar contains an entry for this variant (Variation ID: 328503). Studies have shown that this variant alters JAK3 gene expression (PMID: 11781709). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in retention of 87 nucleotides from intron 19 and introduces a premature termination codon (PMID: 11781709). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000346279	SCV003831811	likely pathogenic	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2022-05-06	criteria provided, single submitter	clinical testing