ClinVar Miner

Submissions for variant NM_000215.4(JAK3):c.187A>G (p.Ile63Val)

gnomAD frequency: 0.00026  dbSNP: rs144405201
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen RCV000639640 SCV004242255 likely benign T-B+ severe combined immunodeficiency due to JAK3 deficiency 2024-01-23 reviewed by expert panel curation The c.187A>G (NM_000215.4) variant in JAK3 is a missense variant predicted to cause the substitution of Isoleucine by Valine at amino acid 63 (p.Ile63Val). The popmax filtering allele frequency (the upper threshold of the 95% CI) of this variant is 0.00007135 (105/1179936 alleles) for European (non-Finnish) chromosomes by gnomAD v.4, which is lower than the ClinGen SCID VCEP threshold (<0.000115) for PM2_Supporting; However, the highest MAF in the Ashkenazi Jewish population is 0.007061 (209/29600 alleles), which is above the SCID VCEP established threshold of >0.00100 for BS1. As this population is not known to have a higher prevalence, this is considered to meet BS1. One homozygote is described in gnomAD v.4 in the Ashkenazi Jewish population (BS2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with JAk3-SCID/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 and BS2_Supporting (VCEP specifications version 1.0).
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000239244 SCV000296885 uncertain significance not specified 2015-07-30 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000639640 SCV000411128 uncertain significance T-B+ severe combined immunodeficiency due to JAK3 deficiency 2018-01-12 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000639640 SCV000761219 likely benign T-B+ severe combined immunodeficiency due to JAK3 deficiency 2025-01-30 criteria provided, single submitter clinical testing

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