Submissions for variant NM_000448.3(RAG1):c.2327G>A (p.Arg776Gln)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282826	SCV002570604	uncertain significance	not specified	2022-07-15	criteria provided, single submitter	clinical testing	Variant summary: RAG1 c.2327G>A (p.Arg776Gln) results in a conservative amino acid change located in the insertion/Zinc binding (ID/ZnB) domain (Ru_2015) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251202 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2327G>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with T-/B-/NK+ SCID (Severe Combined Immunodeficiency) and as a presumed compound heterozygous genotype without phase specified in settings of Primary Immunodeficiency (example, Karaca_2009, cited in Kutukculer_2012, Lee_2017 cited in Lee_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003096337	SCV003440363	pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2024-10-22	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 776 of the RAG1 protein (p.Arg776Gln). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individuals with severe combined immunodeficiency (SCID) (PMID: 17572155, 22424479, 24144642). ClinVar contains an entry for this variant (Variation ID: 1704499). 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. This variant disrupts the p.Arg776 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18701881). 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.
PreventionGenetics, part of Exact Sciences	RCV004529119	SCV004106204	likely pathogenic	RAG1-related disorder	2023-09-15	criteria provided, single submitter	clinical testing	The RAG1 c.2327G>A variant is predicted to result in the amino acid substitution p.Arg776Gln. In the literature this variant is also reported as G2439A and R776Q. This variant was reported in the compound heterozygous state in an individual with T-B-NK+ severe combined Immunodeficiency (SCID) (Karaca et al. 2009. PubMed ID: 19458910; Kutukculer et al. 2012. PubMed ID: 22424479). This variant was also reported in the presumed homozygous state in an individual with SCID, however specific details were not provided (Patient 43, Haq et al. 2007. PubMed ID: 17572155). Of note, another variant impacting the same amino acid (p.Arg776Trp) has been reported in the homozygous state in Athabascan-speaking Dine Indians from the Canadian Northwest Territories with T-B-NK+ SCID (Xiao et al. 2009. PubMed ID: 18701881). The p.Arg776Gln variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-36597181-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from pathogenic to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/1704499/). Taken together we interpret this variant as likely pathogenic.
Baylor Genetics	RCV003475325	SCV004200508	likely pathogenic	Combined immunodeficiency due to partial RAG1 deficiency	2023-05-02	criteria provided, single submitter	clinical testing