Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000526312 | SCV000646365 | likely pathogenic | Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive | 2020-01-03 | criteria provided, single submitter | clinical testing | This variant has been observed in individual(s) with severe combined immunodeficiency or Omenn syndrome with RAG1 reversion mosaicism (PMID: 24290284, 24817258). 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. Experimental studies have shown that this missense change demonstrates disrupted recombination activity (PMID: 24290284, 24817258). 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 RAG1 protein function. Experimental studies have shown that this missense change demonstrates disrupted recombination activity (PMID: 24290284, 24817258). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 411 of the RAG1 protein (p.Leu411Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. |