Submissions for variant NM_000448.3(RAG1):c.2522G>A (p.Arg841Gln)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003062360	SCV003440364	pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2023-10-27	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 841 of the RAG1 protein (p.Arg841Gln). This variant is present in population databases (rs748296558, gnomAD 0.004%). This missense change has been observed in individuals with clinical features of severe combined immunodeficiency (PMID: 23891352, 32655540, 32888943). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2137056). 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: 23891352, 24290284, 32655540). This variant disrupts the p.Arg841 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19246248, 24144642, 24290284, 28769923, 30307608). 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.
Revvity Omics, Revvity	RCV003130813	SCV003811452	likely pathogenic	not provided	2023-01-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317640	SCV004020621	pathogenic	Severe combined immunodeficiency disease	2023-06-02	criteria provided, single submitter	clinical testing	Variant summary: RAG1 c.2522G>A (p.Arg841Gln) results in a conservative amino acid change to a highly conserved residue (HGMD) in the encoded protein sequence. Another missense variant (p.Arg841Trp) affecting the same amino acid is classified as pathogenic in ClinVar. 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 8e-06 in 250952 control chromosomes (gnomAD). c.2522G>A has been reported in the literature in individuals affected with Severe Combined Immunodeficiency or primary immunodeficiency (Henderson_2013, Platt_2021, Sharapova_2020), and these patients were reported as compound heterozygous with other RAG1 variants, one of which is classified as pathogenic in ClinVar. These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function in cells containing vectors with the variant, resulting in loss of RAG1 protein expression and ~0% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 23891352, 32655540, 32888943). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003475495	SCV004200473	likely pathogenic	Combined immunodeficiency due to partial RAG1 deficiency	2024-03-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005045199	SCV005683492	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	2024-03-12	criteria provided, single submitter	clinical testing