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

gnomAD frequency: 0.00009  dbSNP: rs193922461

Total submissions: 8

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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000696949	SCV000825533	pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2025-01-21	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). Invitae Evidence 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 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
Mayo Clinic Laboratories, Mayo Clinic	RCV000519696	SCV005413976	pathogenic	not provided	2024-03-08	criteria provided, single submitter	clinical testing	PP3, PM3_very_strong, PS3
Fulgent Genetics, Fulgent Genetics	RCV005042097	SCV005683468	pathogenic	Combined immunodeficiency due to partial RAG1 deficiency; Combined immunodeficiency with skin granulomas; Histiocytic medullary reticulosis; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2024-03-04	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).