Submissions for variant NM_000536.4(RAG2):c.1198G>C (p.Asp400His)

gnomAD frequency: 0.00058  dbSNP: rs140682926

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000556982	SCV000646379	uncertain significance	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 400 of the RAG2 protein (p.Asp400His). This variant is present in population databases (rs140682926, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with combined immunodeficiency (CID) (PMID: 28769923). ClinVar contains an entry for this variant (Variation ID: 469117). 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. Experimental studies have shown that this missense change affects RAG2 function (PMID: 23994475). 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.
Illumina Laboratory Services, Illumina	RCV001104247	SCV001261097	uncertain significance	Histiocytic medullary reticulosis	2017-07-11	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001104248	SCV001261098	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2017-07-11	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Natera, Inc.	RCV001104247	SCV001456091	uncertain significance	Histiocytic medullary reticulosis	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003935477	SCV004756573	uncertain significance	RAG2-related disorder	2023-11-07	no assertion criteria provided	clinical testing	The RAG2 c.1198G>C variant is predicted to result in the amino acid substitution p.Asp400His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.094% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-36614521-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.