Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| 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 | 2023-12-11 | 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 (Invitae). ClinVar contains an entry for this variant (Variation ID: 843920). 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) performed at Invitae 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004702599 | SCV005203430 | uncertain significance | not specified | 2024-07-18 | 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. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251278 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.419A>G has been reported in the literature as compound heterozygous genotype in an individual affected with Severe Combined Immunodeficiency (Tanita_2022, Wakamatsu_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency. 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 uncertain significance. |
| Natera, |
RCV001832439 | SCV002087160 | uncertain significance | Histiocytic medullary reticulosis | 2021-08-05 | no assertion criteria provided | clinical testing |