Submissions for variant NM_000536.4(RAG2):c.217C>G (p.Arg73Gly)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003031080	SCV003314234	likely pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2022-08-04	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Arg73 amino acid residue in RAG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20603253, 24481607, 26476733; Invitae). 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. This missense change has been observed in individual(s) with severe combined immunodeficiency due to RAG2 deficiency (PMID: 32531373). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 73 of the RAG2 protein (p.Arg73Gly). This variant is not present in population databases (gnomAD no frequency).