ClinVar Miner

Submissions for variant NM_000448.2(RAG1):c.1566G>T (p.Trp522Cys) (rs193922461)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519696 SCV000616850 pathogenic not provided 2017-10-20 criteria provided, single submitter clinical testing The W522C variant in the RAG1 gene has been reported previously, along with a second variant, in multiple unrelated individuals with immunodeficiency (Villa et al., 2011; De et al., 2010; Buchbinder et al., 2015). The W522C variant is observed in 28/126314 (0.02%) alleles from individuals of non-Finnish European background, in the ExAC dataset, and no individuals were reported to be homozygous (Lek et al., 2016). The W522C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies demonstrated a 42% decrease in recombination activity, assessed by induction of the Ighc locus rearrangements in RAG1 knockout mice, compared to wild type (Lee et al., 2014). Therefore, we interpret W522C as a pathogenic variant.
Invitae RCV000696949 SCV000825533 pathogenic Combined cellular and humoral immune defects with granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2018-07-24 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 522 of the RAG1 protein (p.Trp522Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is present in population databases (rs193922461, ExAC 0.02%). This variant has also been observed in several individuals affected with atypical SCID/Omenn syndrome (OS) and delayed-onset combined immune deficiency (CID) (PMID: 11133745, 25516070, 24290284, 10701853). This variant has also been observed in an individual affected with midline granulomatous disease (PMID: 20489056). ClinVar contains an entry for this variant (Variation ID: 36710). An experimental study has shown that this missense change results in decreased RAG1 recombinase activity (PMID: 20489056). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000022745 SCV000044034 pathogenic Combined cellular and humoral immune defects with granulomas 2010-08-26 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000022745 SCV000053058 likely pathogenic Combined cellular and humoral immune defects with granulomas 2015-10-02 no assertion criteria provided clinical testing The c.1566G>T (p.Trp522Cys) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a pathogenic outcome. The variant is present at a low frequency in the control population (0.01% in ExAC), but has been reported in the literature in patients with granulomatous disease (De Ravin_2010), atypical SCID/OS (Villa_2000, Kwan_2013) and common variable immunodeficiency (Lee_2014, Buchbinder_2014). In vitro analysis showed the variant to result in recombination acitivty that was 50-60% reduced compared to WT (De Ravin_2010, Lee_2014).

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