Submissions for variant NM_000448.3(RAG1):c.2245A>G (p.Ile749Val)

gnomAD frequency: 0.00003  dbSNP: rs542851147

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001928974	SCV002206512	uncertain significance	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2021-09-02	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with valine at codon 749 of the RAG1 protein (p.Ile749Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs542851147, ExAC 0.03%). This variant has not been reported in the literature in individuals affected with RAG1-related conditions. 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 not expected to disrupt RAG1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.