ClinVar Miner

Submissions for variant NM_000215.4(JAK3):c.3217C>T (p.Leu1073Phe)

gnomAD frequency: 0.00036  dbSNP: rs200580168
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001068240 SCV001233338 uncertain significance T-B+ severe combined immunodeficiency due to JAK3 deficiency 2022-08-06 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1073 of the JAK3 protein (p.Leu1073Phe). This variant is present in population databases (rs200580168, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with JAK3-related conditions. ClinVar contains an entry for this variant (Variation ID: 861674). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Illumina Laboratory Services, Illumina RCV001068240 SCV001287806 uncertain significance T-B+ severe combined immunodeficiency due to JAK3 deficiency 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Neuberg Centre For Genomic Medicine, NCGM RCV001068240 SCV005442705 uncertain significance T-B+ severe combined immunodeficiency due to JAK3 deficiency 2023-07-22 criteria provided, single submitter clinical testing The missense variant c.3217C>T p.Leu1073Phe in the JAK3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.04% in the gnomAD Exomes. The amino acid Leu at position 1073 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The amino acid change p.Leu1073Phe in JAK3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

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