Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV003058302 | SCV003439690 | likely pathogenic | Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive | 2023-09-22 | 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 699 of the RAG1 protein (p.Arg699Gln). This variant is present in population databases (rs369990217, gnomAD 0.01%). This missense change has been observed in individual(s) with combined immune deficiency (PMID: 24290284). ClinVar contains an entry for this variant (Variation ID: 2137055). 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: 24290284). This variant disrupts the p.Arg699 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20956421, 21184155, 21771083, 24122031, 24290284). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |