Submissions for variant NM_000448.3(RAG1):c.1210C>T (p.Arg404Trp)

dbSNP: rs764981110

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000788766	SCV000928002	likely pathogenic	not provided	2018-10-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000817183	SCV000957730	pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2023-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 404 of the RAG1 protein (p.Arg404Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Omenn syndrome and with clinical features of severe combined immunodeficiency (PMID: 11313270, 26829731; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as C1322T, c.1209C>T (p.R403W). ClinVar contains an entry for this variant (Variation ID: 636824). 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: 11313270). This variant disrupts the p.Arg404 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12200379, 16960852, 24290284, 24985406). 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	RCV003226392	SCV003922669	pathogenic	Severe combined immunodeficiency disease	2023-03-30	criteria provided, single submitter	clinical testing	Variant summary: RAG1 c.1210C>T (p.Arg404Trp) results in a non-conservative amino acid change located in the RAG nonamer-binding domain (IPR023336) of the encoded protein sequence. Five 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 250788 control chromosomes (gnomAD). c.1210C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Severe Combined Immunodeficiency Syndrome/Omenn Syndrome (e.g. Corneo_2001, Melika_2021, Cifaldi_2022, Aykut_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant resulted in a dramatically reduced recombination frequency compared to the WT protein (e.g. Corneo_2001). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004538084	SCV004106003	pathogenic	RAG1-related disorder	2023-02-21	criteria provided, single submitter	clinical testing	The RAG1 c.1210C>T variant is predicted to result in the amino acid substitution p.Arg404Trp. This variant was reported in the compound heterozygous, suspected compound heterozygous, or homozygous state in individuals with RAG deficiencies such as Omenn syndrome or severe combined immunodeficiency (Corneo et al. 2001. PubMed ID: 11313270; Sobacchi et al. 2006. PubMed ID: 16960852; Supplementary Table 2, Platt et al. 2020. PubMed ID: 32888943; Melika et al. 2021. PubMed ID: 34224223). The p.Arg404Trp change has been shown to disrupt RAG protein recombination activity in vitro (Corneo et al. 2001. PubMed ID: 11313270). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-36596064-C-T). This variant is interpreted as pathogenic.
Baylor Genetics	RCV003472327	SCV004200486	pathogenic	Combined immunodeficiency due to partial RAG1 deficiency	2023-11-25	criteria provided, single submitter	clinical testing