Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV005912480 | SCV005203430 | likely pathogenic | Severe combined immunodeficiency disease | 2025-07-31 | criteria provided, single submitter | clinical testing | Variant summary: RAG2 c.419A>G (p.His140Arg) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 251278 control chromosomes. c.419A>G has been reported in individuals affected with Severe Combined Immunodeficiency (Tanita_2022, Wakamatsu_2022, internal data). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35281013, 35902420). ClinVar contains an entry for this variant (Variation ID: 843920). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Labcorp Genetics |
RCV001046638 | SCV001210548 | likely pathogenic | Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive | 2025-02-04 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 140 of the RAG2 protein (p.His140Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of severe combined immunodeficiency (PMID: 35281013; internal data). ClinVar contains an entry for this variant (Variation ID: 843920). 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) indicates that this missense variant is expected to disrupt RAG2 protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Natera, |
RCV001832439 | SCV002087160 | uncertain significance | Histiocytic medullary reticulosis | 2021-08-05 | no assertion criteria provided | clinical testing |