ClinVar Miner

Submissions for variant NM_016123.4(IRAK4):c.34C>T (p.Arg12Cys)

gnomAD frequency: 0.00001  dbSNP: rs377584435
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497500 SCV000589640 likely pathogenic not provided 2017-06-20 criteria provided, single submitter clinical testing The R12C variant in the IRAK4 gene has been reported previously in child with recurrent pyogenic bacterial infections who was compound heterozygous for the R12C variant and another variant (Hoarau et al., 2007). Functional studies showed recombinant R12C IRAK4 protein failed to interact with MyD88 protein (Yamamoto et al., 2014). The R12C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R12C variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R12C as a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV000023583 SCV001422147 uncertain significance Immunodeficiency 67 2022-08-23 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 12 of the IRAK4 protein (p.Arg12Cys). This variant is present in population databases (rs377584435, gnomAD 0.007%). This missense change has been observed in individual(s) with IRAK-4 deficiency (PMID: 17878374). ClinVar contains an entry for this variant (Variation ID: 30609). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects IRAK4 function (PMID: 24316379, 33083971). 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.
OMIM RCV000023583 SCV000044874 pathogenic Immunodeficiency 67 2007-10-01 no assertion criteria provided literature only

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