ClinVar Miner

Submissions for variant NM_016123.4(IRAK4):c.547C>T (p.Arg183Ter)

gnomAD frequency: 0.00008  dbSNP: rs114951157
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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 RCV000687372 SCV000814936 pathogenic Immunodeficiency 67 2023-11-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg183*) in the IRAK4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IRAK4 are known to be pathogenic (PMID: 17893200, 21057262). This variant is present in population databases (rs114951157, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with IRAK4 deficiency (PMID: 21057262). ClinVar contains an entry for this variant (Variation ID: 567326). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM RCV000687372 SCV005060952 likely pathogenic Immunodeficiency 67 criteria provided, single submitter clinical testing The stop gain c.547C>T (p.Arg183Ter) variant in IRAK4 gene has been reported previously in individuals affected with IRAK4 deficiency (Picard et al. 2010; Yamamoto et al. 2014). This variant is reported with an allele frequency of 0.002% in the gnomAD exomes database. This variant has been reported to the ClinVar database as Pathogenic, but no details for independent assessment. The nucleotide change c.547C>T in IRAK4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation, leading to a smaller protein than the wild-type (Yamamoto et al. 2014). Loss of function variants in IRAK4 gene have been previously reported to be disease causing. Additional functional studies are required to prove the pathogenicity of this variant, for these reasons, this variant has been classified as Likely Pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc RCV000687372 SCV005415712 pathogenic Immunodeficiency 67 criteria provided, single submitter clinical testing PM2_Supporting+PVS1+PM3

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