ClinVar Miner

Submissions for variant NM_000448.3(RAG1):c.1566G>T (p.Trp522Cys)

gnomAD frequency: 0.00009  dbSNP: rs193922461
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519696 SCV000616850 pathogenic not provided 2023-06-23 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect, including decreased RAG complex recombination activity (Lee et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25976673, 11133745, 35753512, 25516070, 28783691, 33239578, 34426522, 10701853, 28973083, 24290284, 20489056, 33193364, 26996199, 11971977, 27825771)
Invitae RCV000696949 SCV000825533 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2024-01-08 criteria provided, single submitter clinical testing This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 522 of the RAG1 protein (p.Trp522Cys). This variant is present in population databases (rs193922461, gnomAD 0.02%). This missense change has been observed in individual(s) with atypical SCID/Omenn syndrome (OS) and delayed-onset combined immune deficiency (CID) and midline granulomatous disease (PMID: 10701853, 11133745, 20489056, 24290284, 25516070). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 36710). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAG1 protein function. Experimental studies have shown that this missense change affects RAG1 function (PMID: 20489056). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000519696 SCV003819066 pathogenic not provided 2022-02-03 criteria provided, single submitter clinical testing
Baylor Genetics RCV003473148 SCV004200461 pathogenic Combined immunodeficiency due to partial RAG1 deficiency 2024-03-24 criteria provided, single submitter clinical testing
OMIM RCV000022745 SCV000044034 pathogenic Combined immunodeficiency with skin granulomas 2010-08-26 no assertion criteria provided literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000022745 SCV000053058 likely pathogenic Combined immunodeficiency with skin 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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