Submissions for variant NM_000215.4(JAK3):c.938G>A (p.Gly313Glu)

dbSNP: rs200319694

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000908683	SCV004242261	likely benign	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2024-01-23	reviewed by expert panel	curation	The c.938G>A (NM_000215.4) variant in JAK3 is a missense variant predicted to cause the substitution of Glycine by Glutamic Acid at amino acid 313 (p.Gly313Glu). The filtering allele frequency (the lower threshold of the 95% CI of 90/30614) of the c.938G>A variant in JAK3 is 0.002449 for South Asian chromosomes by gnomAD v2.1., which is higher than the ClinGen SCID VCEP threshold (>0.001) for BS1, and therefore meets this criterion (BS1). No homozygotes have been observed in gnomAD. (BS2 is not met). To our knowledge, this variant has not been reported in the literature in individuals affected with JAK3-related conditions or in functional studies. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS1 (VCEP specifications version 1.0).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000908683	SCV001053460	likely benign	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2024-07-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000908683	SCV001285696	uncertain significance	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000908683	SCV002495811	uncertain significance	T-B+ severe combined immunodeficiency due to JAK3 deficiency	2022-01-27	criteria provided, single submitter	clinical testing	JAK3 NM_000215.3 exon 7 p.Gly313Glu (c.938G>A): This variant has not been reported in the literature but is present in 0.3% (15/4832) of South Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/19-17841686-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:733403). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.