Submissions for variant NM_000448.3(RAG1):c.2333G>A (p.Arg778Gln)

gnomAD frequency: 0.00001  dbSNP: rs121918569

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479659	SCV000568504	pathogenic	not provided	2017-03-14	criteria provided, single submitter	clinical testing	The R778Q variant has been published previously in association with RAG1-associated disorders (Schuetz et al., 2008; Nijman et al., 2014; Kumánovics et al., 2017). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R778Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species; in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. However, functional studies have shown R778Q significantly reduces V(D)J recombination activity in comparison to wild-type (Schuetz et al., 2008; Lee et al., 2014). Additionally, missense variants in the same codon (R778G/W) and in a nearby residue (R776W/Q) have been reported in the Human Gene Mutation Database in association with RAG1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513032	SCV003439726	pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2023-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 778 of the RAG1 protein (p.Arg778Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with "leaky" SCID and/or severe combined immunodeficiency (SCID) (PMID: 18463379, 24290284, 27609655, 33628209). 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: 13158). 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: 24290284). This variant disrupts the p.Arg778 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16960852, 24144642, 24290284, 26476733; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230361	SCV003928986	pathogenic	Severe combined immunodeficiency disease	2023-04-28	criteria provided, single submitter	clinical testing	Variant summary: RAG1 c.2333G>A (p.Arg778Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251206 control chromosomes. c.2333G>A has been reported in the literature in homozygote and compound heterozygote individuals affected with Severe Combined Immunodeficiency (examples: Scheutz_2008, Kumanovics_2017, Vignesh_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal VDJ recombination activity (examples: Scheutz_2008, Lee_2014). The following publications have been ascertained in the context of this evaluation (PMID: 27609655, 24290284, 18463379, 33628209). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV004566741	SCV005054056	pathogenic	Combined immunodeficiency due to partial RAG1 deficiency	2024-02-17	criteria provided, single submitter	clinical testing
OMIM	RCV000014044	SCV000034291	pathogenic	Combined immunodeficiency with skin granulomas	2008-05-08	no assertion criteria provided	literature only